JASPAC 01 protocol

JASPAC 01
Pharma Valley Center Clinical Research Development ProjectJapan Adjuvant Study Group of Pancreatic Cancer (JASPAC)

Protocol for comparative phase III trial of gemcitabine versus
S-1 as adjuvant chemotherapy in patients with resectedpancreatic cancer
Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 inpatients with resected pancreatic cancer

Study Representative: Katsuhiko Uesaka
Department Head, Department of Hepato-Biliary-Pancreatic
Surgery, Shizuoka Cancer Center
1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka,
411-8777Tel
055-989-5222
Fax
055-989-5634
E-mailk.uesaka@scchr.jp
Study Administrators: Yukiyasu Okamura
Chief Physician, Department of Hepato-Biliary-Pancreatic
Surgery, Shizuoka Cancer Center
E-mailyu.okamura@scchr.jp
Akira Fukutomi
Chief Physician, Department of Gastrointestinal Oncology,
Shizuoka Cancer Center
E-maila.fukutomi@scchr.jp
Protocol Version 1 Prepared on: January 12, 2007
Protocol Version 1.1 Prepared on: January 26, 2007
Protocol Version 1.2 Prepared on: April 2, 2007
Protocol Version 1.3 Prepared on: July 28, 2008
Protocol Version 1.4 Prepared on: April 27, 2013
Protocol Version 1.41 Prepared on: June 10, 2014
Protocol Version 1.42 Prepared on: March 23, 2014

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0. Synopsis
0.1.

OutlineResected pancreatic cancer
R0-1, ≥20 years of age, PS0-1
No previous chemotherapy or radiation therapy

Random assignment
Assignment adjustment factors: R0/1, N0/1, study site

Arm A: Gemcitabine therapy

Arm B: S-1 therapy

2

Gemcitabine at 1000 mg/m d.i.v. on days 1, 8 and 15

TS-1 at 80 mg/m2/day on days 1-28

1 course = 4 weeks, for 6 months

1 course = 6 weeks, for 6 months

X-ray and CT evaluation until confirmation of relapse
Every 3 months within 2 years following registration
Every 6 months from 2 years following registration

0.2. Objectives
To verify in terms of overall survival the non-inferiority of S-1 therapy against gemcitabine
therapy as adjuvant chemotherapy after resected pancreatic cancer.
Primary Endpoint: Overall survival
Secondary Endpoints: Incidence of adverse events, relapse-free survival, health-related qualityof life (HRQOL)JASPAC 01

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0.3. Subjects
1) Patients with resected pancreatic cancer that was a histologically verified invasive ductal
carcinoma of the pancreas (based on Classification of Pancreatic Carcinoma 5th Edition 21, but
excluding cystadenocarcinoma).
2) Patients with macroscopic total resection of the primary tumor, and residual primary tumor thatsatisfies all of the below according to the UICC 6th Edition22 histopathologic staging system.
・Stage II or lower, or stage III where resection included the celiac artery・Local residual tumor classified as R0 or R1・Cytologic examination negative upon intraoperative peritoneal lavage
3) Absence of distant metastases and malignant ascites
4) Adequate oral intake is possible5) Age of 20 years or above
6) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
7) Absence of chemotherapy or radiotherapy within past 3 years8) Within 10 weeks following resection of pancreatic cancer
9) Major organ functions adequately conserved as shown below (bone marrow, lungs, kidneys)
Satisfies all the criteria below in measurements taken from 7 days prior to registration
・White blood cell count: ≥3,000/mm3, ≤12,000/mm3
・Platelet count: ≥100,000/mm3
・Hemoglobin: ≥8.0 g/dL
・Total bilirubin: ≤2.0 mg/dL
・Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤100 IU/L・Serum creatinine: ≤1.2 mg/dL
10) Written informed consent given
0.4. Treatment
Arm A: Gemcitabine therapy
Gemcitabine at 1000 mg/m2 d.i.v. Administered on days 1, 8 and 15. One course =4 weeks.
Treatment for 6 months or until confirmation of recurrence
Arm B: S-1 therapy
TS-1 at 80mg/m2/day. Administered on days 1-28. One course = 6 weeks.
Four courses of treatment or until confirmation of recurrence
0.5. Planned number of registered patients and study period
Planned number of registered patients: 360.
Registration period: 3 years and 3 months. Follow-up period: 5 years after end of registration(by June 30th 2015). Review period after follow-up period: 1year. Total study period: 9 years 3
months.
0.6. Contact details
Matters that require clinical judgment, such as eligibility criteria and criteria for change oftreatment: Study administrators (Cover page, 17.2)
Registration procedure, filling records forms (case report forms), etc.: Study administrators(Cover page, 17.2), CSPOR data center (17.7)
Adverse event reports: Study administrators/study representative, CSPOR data center (17.7)

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0.

SYNOPSIS ....................................................................................................................................21.

OBJECTIVES ...............................................................................................................................72.

BACKGROUND AND RATIONALE FOR THE STUDY PLAN ......................................................8
2.1.
2.2.
2.3.
2.4.
2.5.
2.6.
2.7.

3.

STANDARDS AND DEFINITIONS USED IN THIS STUDY .........................................................14
3.1.
3.2.
3.3.

4.

PROTOCOL TREATMENT ................................................................................................ 21
CRITERIA FOR PROTOCOL TREATMENT COMPLETION AND DISCONTINUATION ........................... 22
TREATMENT CHANGE CRITERIA ...................................................................................... 23
CONCOMITANT THERAPIES/SUPPORTIVE THERAPIES ........................................................... 31
POSTTREATMENT ......................................................................................................... 33

DRUG INFORMATION AND ANTICIPATED ADVERSE REACTIONS ......................................34
7.1.
7.2.
7.3.

8.

REGISTRATION PROCEDURE ........................................................................................... 19
RANDOM ASSIGNMENT AND ASSIGNMENT ADJUSTMENT FACTORS ........................................... 19
REPORTING OF REGISTRATION CONFIRMATION AND THE PRE-TREATMENT REPORT ................... 20

TREATMENT PLAN AND TREATMENT CHANGE CRITERIA ................................................21
6.1.
6.2.
6.3.
6.4.
6.5.

7.

ELIGIBILITY CRITERIA (ENROLMENT CRITERIA) ................................................................. 17
EXCLUSION CRITERIA ................................................................................................... 18

REGISTRATION AND ASSIGNMENT........................................................................................19
5.1.
5.2.
5.3.

6.

HISTOLOGY CLASSIFICATION .......................................................................................... 14
CANCER STAGING ......................................................................................................... 14
REGIONAL LYMPH NODES .............................................................................................. 15

PATIENT SELECTION CRITERIA ............................................................................................17
4.1.
4.2.

5.

TARGET DISEASE ............................................................................................................8
STANDARD TREATMENTS FOR THE TARGET DISEASE ..............................................................8
PROTOCOL TREATMENTS .................................................................................................9RATIONALE FOR THE STUDY PLAN.................................................................................... 10
SUMMARY OF ANTICIPATED BENEFITS AND DISADVANTAGES OF PARTICIPATION IN THE STUDY ..... 12
SIGNIFICANCE OF THIS STUDY ......................................................................................... 13
ANCILLARY RESEARCH .................................................................................................. 13

DRUG INFORMATION ..................................................................................................... 34
ANTICIPATED ADVERSE EVENTS ...................................................................................... 41
EVALUATION OF ADVERSE EVENTS/ADVERSE DRUG REACTIONS.............................................. 42

ITEMS FOR EVALUATION, LABORATORY TESTS AND EVALUATION SCHEDULE ............44
8.1.
8.2.
8.3.
8.4.
8.5.

ITEMS EVALUATED PRIOR TO REGISTRATION ..................................................................... 44
CATEGORIZATION OF TREATMENT PERIOD, OBSERVATION PERIOD AND FOLLOW-UP PERIOD........ 44
INVESTIGATIONS AND EVALUATIONS DURING THE TREATMENT PERIOD ................................... 45
INVESTIGATIONS AND EVALUATIONS DURING THE OBSERVATION PERIOD ................................. 45
INVESTIGATIONS AND EVALUATIONS DURING THE FOLLOW-UP PERIOD .................................... 46

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8.6.

STUDY CALENDAR ........................................................................................................ 47

DATA COLLECTION .................................................................................................................48

9.

9.1.
10.

REPORTING OF ADVERSE EVENTS ......................................................................................51

10.1.
10.2.
10.3.
10.4.
11.

DEFINITION OF THE ANALYSIS POPULATION ...................................................................... 54
ENDPOINT DEFINITIONS ................................................................................................ 54

HEALTH-RELATED QOL ........................................................................................................56

12.1.
12.2.
12.3.
12.4.
12.5.
12.6.
13.

ADVERSE EVENTS OF WHICH THERE IS AN OBLIGATION TO REPORT ....................................... 51
REPORTING OBLIGATIONS OF THE STUDY SITE STUDY MANAGER AND REPORTING PROCEDURES .. 52
RESPONSIBILITIES OF THE STUDY REPRESENTATIVE/STUDY ADMINISTRATORS ......................... 52
EXAMINATION BY THE EFFICACY AND SAFETY EVALUATION COMMITTEE .............................. 53

ASSESSMENT OF EFFICACY AND DEFINITION OF ENDPOINTS .........................................54

11.1.
11.2.
12.

RECORDS FORMS (CASE REPORT FORMS: CRFS) ................................................................. 48

OBJECTIVES ............................................................................................................... 56
HRQOL SCALE .......................................................................................................... 56
HRQOL SURVEY SCHEDULE.......................................................................................... 56
SURVEY METHOD ........................................................................................................ 56
SAMPLE SIZE .............................................................................................................. 56
METHOD OF DATA ANALYSIS ......................................................................................... 56

STATISTICAL CONSIDERATIONS..........................................................................................57

13.1. MAIN ANALYSES AND EVALUATION CRITERIA .................................................................... 57
13.2. PLANNED SAMPLE SIZE AND FOLLOW-UP PERIOD ............................................................... 57
13.3. PATIENT HANDLING, ANALYSIS POPULATION AND DATA ANALYSIS ......................................... 58
13.4. SUMMARIZING PATIENT REGISTRATION ........................................................................... 58
13.5. SUMMARIZING AND COMPARING TREATMENT COMPLIANCE ................................................. 58
13.6. ANALYSIS OF SURVIVAL TIMES ....................................................................................... 58
13.7. SUPPLEMENTAL ANALYSIS OF SURVIVAL TIMES ................................................................. 59
13.8. ANALYSIS OF THE IMPACT OF SECONDARY TREATMENTS ON OVERALL SURVIVAL ..................... 59
13.9. ANALYSIS OF ADVERSE EVENTS ...................................................................................... 59
13.10. OTHER ANALYSES ....................................................................................................... 59
13.11. BLINDED MONITORING ................................................................................................. 59
13.12. INTERIM ANALYSIS ...................................................................................................... 59
14.

ETHICAL CONSIDERATIONS .................................................................................................61

14.1.
14.2.
14.3.
14.4.
14.5.
14.6.
15.

PATIENT PROTECTION .................................................................................................. 61
INFORMED CONSENT .................................................................................................... 61
PROTECTION OF PRIVACY AND PATIENT IDENTIFICATION .................................................... 62
PROTOCOL VIOLATIONS ............................................................................................... 62
APPROVAL OF THE STUDY SITE ETHICAL REVIEW BOARD (INSTITUTIONAL REVIEW BOARD) ........ 62
CHANGES TO THE PROTOCOL......................................................................................... 64

MONITORING AND AUDIT .....................................................................................................67

15.1.
15.2.

PERIODIC MONITORING ................................................................................................ 67
STUDY SITE VISIT AND AUDIT ......................................................................................... 68

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16.

NOTICE ....................................................................................................................................69

17.

STUDY ORGANIZATION .........................................................................................................70

17.1.
17.2.
17.3.
17.4.
17.5.
17.6.
17.7.
17.8.
17.9.

STUDY REPRESENTATIVE .............................................................................................. 70
STUDY ADMINISTRATORS .............................................................................................. 70
STEERING ADMINISTRATOR .......................................................................................... 70
PARTICIPATING STUDY SITES ......................................................................................... 71
STEERING COMMITTEE ................................................................................................ 73
EFFICACY AND SAFETY EVALUATION COMMITTEE ............................................................ 73
STUDY STATISTICIAN (MANAGER OF BIOSTATISTICAL ANALYSIS)........................................... 73
DATA CENTER ............................................................................................................ 73
PROTOCOL DRAFTING COMMITTEE ................................................................................ 73

18.

PRESENTATION OF STUDY RESULTS ...................................................................................74

19.

REFERENCES ..........................................................................................................................75

20.

APPENDIX ...............................................................................................................................76

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1. Objectives
To verify the non-inferiority of S-1 therapy against gemcitabine as adjuvant chemotherapy forresected pancreatic cancer in terms of overall survival.
Primary Endpoint: Overall survival
Secondary Endpoints: Incidence of adverse events, relapse-free survival, health-related qualityof life (HRQOL)JASPAC 01

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2. Background and rationale for the study plan
2.1.

Target disease

The number of deaths caused by pancreatic cancer is increasing every year in Japan, withapproximately 23,000 deaths caused by pancreatic cancer in 2005. This accounts for 7.0% of
deaths caused by cancer in Japan, placing it 5th among causes of cancer death after lung, stomach,colon and liver cancers1.
Although surgical resection is the only curative treatment option for pancreatic cancer, only
approximately 10-20% of cases are resectable2-3. Even when resection is performed, there is areported 95% rate of recurrence within 2 years of surgery4, a median overall survival of 11-16.9
months and a 5-year survival rate of just 8-18%5-9. Development of a more effective, multimodal
treatment is necessary as resection alone provides limited results in terms of therapeutic outcome.
2.2.

Standard treatments for the target disease

Postoperative adjuvant therapies have been developed to improve treatment outcomes forresected pancreatic cancers.
The first prospective study of adjuvant radiochemotherapy for pancreatic cancer (GITSG 9173)
reported an improvement in overall survival in a group given combined 5-Fluorouracil (5-FU) andconcurrent radiotherapy compared to an observation group (MST: 20 months compared to 11
months, P = 0.03)5. This study was terminated, however, after less than half of the planned
registered subjects was reached after a significant improvement in overall survival was observed at
an interim analysis, and due to the time required for patient accrual. Furthermore, because many
subjects deviated from the prescribed treatment in the study and 5-FU administration was
continued for 2 years after ending radiochemotherapy, there were doubts as to the clinicalsignificance of adjuvant radiochemotherapy shown in this study. Acknowledging the results of thisstudy, a large-scale comparative study (EORTC) that limited the duration 5-FU treatment to theduration of radiotherapy and was a well-managed study of good quality observed no significant
difference in overall survival between a combined 5-FU and radiotherapy group and an observationgroup (MST: 17.1 months and 12.6 months, P = 0.099)6.
Another study compared an adjuvant chemotherapy of combined 5-FU, doxorubicin andmitomycin C (FAM) with just observation, reporting an improvement in overall survival in the
FAM group over the observation group (MST: 23 months and 11 months, P = 0.02). However, in
this study no difference in the 2-year survival rate was observed (2-year survival rate: 43% and32%, P = 0.10) and severe toxicity was observed in the FAM group7.
Another large-scale study (ESPAC-1) investigated both adjuvant chemotherapy and adjuvant
radiochemotherapy, dividing subjects into a concomitant 5-FU and radiotherapy group (1),chemotherapy (5-FU and folonic acid) group (2), combined therapy ((2) following (1)) group (3),and observation group (4). Overall survival was improved in patients who received any
chemotherapy (groups (2) and (3)) over those who received no chemotherapy (groups (1) and (4))
(MST: 20.1 months and 15.5 months, P = 0.009), while overall survival was inferior in patients
who received radiochemotherapy (groups (1) and (3)) compared to those who received noradiochemotherapy (groups (2) and (4)) (MST: 15.9 months and 17.9 months, P = 0.05)8. However,there was probably bias in the results of this study since it employed a complex method of
examination, there was no significant difference in overall survival between the individual groups,
and it was possible to choose what kind of comparison was examined (radiochemotherapy only
and chemotherapy only).
Gemcitabine (GEM) started to be used in studies of postoperative adjuvant therapies in 1997,
when it was shown that GEM was significantly more beneficial than 5-FU for the treatment ofpatients with unresectable advanced pancreatic cancers and distant metastases10. In the 2006 ASCO
Annual Meeting, a study was reported that compared the administration of GEM or 5-FU before

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and after concomitant 5-FU and radiotherapy (RTOG-9704), and improved overall survival using
GEM treatment over 5-FU treatment was only found in patients with pancreatic head cancer (MST:
20.6 months and 16.9 months, P = 0.33)11. A study published in January 2007 that comparedadjuvant chemotherapy using GEM and just observation (CONKO-001) reported an improvement
in relapse-free survival in the GEM group (DFS: 13.4 months compared with 6.9 months, P <0.001)12.
Currently ongoing is a study that compares GEM therapy, 5-FU + folinic acid therapy andobservation (ESPAC-3) and a study that compares GEM therapy only and combined GEM andradiotherapy (EORTC-40013). The ESPAC-3 study terminated its observation group based on the
results of the ESPAC-1 study, so that both the above ESPAC-3 and EORTC-40013 studies have noobservation group and are using GEM as the control group.
2.3.

Protocol treatments

2.3.1. Drugsa) Gemcitabine (Generic name: Gemzar®)
Gemcitabine is classified as an antimetabolite anticancer agent. It is metabolized intracellularly
to gemcitabine triphosphate and inhibits DNA synthesis. The concentration of gemcitabine
triphosphate is maintained intracellularly for a long period and it exhibits a strong cytocidal action
against solid cancer13-15. In Japan, its use for non-small cell lung cancer, pancreatic cancer andbiliary tract cancer is approved for health insurance coverage.
b) S-1 (Generic name: TS-1®)
S-1 is an oral fluorinated pyrimidine anticancer drug that contains tegafur (FT, a prodrug of
5-FU), gimeracil (CDHP, an inhibitor of the enzyme that degrades 5-FU) and oteracil potassium(Oxo, phosphorylation inhibitor). Including gimeracil and oteracil potassium increases the
maximum concentration of 5-FU in the blood, enhancing its antitumor effect and mitigating its
gastrointestinal toxicity16-18. In Japan, its use for gastric cancer, head and neck cancer, colorectal
cancer, non-small cell lung cancer, inoperable or recurrent breast cancer and pancreatic cancer isapproved for health insurance coverage.
2.3.2. Treatment regimena) Gemcitabine therapy
The dosage and administration approved in Japan will be used. That is, “1,000 mg/m2
administered by 30-minute intravenous infusion, administered once per week for 3 weeks, followed
by a 1-week rest period.”
In a phase I trial conducted in Japan19, the dosage was fixed at 1,000 mg/m2 and escalated via
two administration schedules. Dose-limiting toxicity (DLT) was not observed during administration
schedule 1 (1,000 mg/m2/30 minutes/once per week for 3 weeks, followed by a 1-week rest period).
Out of 6 patients on administration schedule 2 (1,000 mg/m2/30 minutes/once per week for 7 weeks
followed by a 1-week rest period, then administration for 3 weeks followed by a 1-week rest period
thereafter) one patient experienced grade 4 leukocytopenia and grade 4 neutropenia, and one
patient experienced grade 4 neutropenia and grade 3 hepatic dysfunction. Administration schedule
1 was chosen as the standard dosage and administration. Adverse events of grade 3 or higher
observed in the trial were leukocytopenia, neutropenia, anorexia, fatigue and nausea/vomiting.
Of 384 patients administered gemcitabine monotherapy in Japanese clinical studies, the main
adverse drug reactions observed in a safety population including 369 patients have been
leukocytopenia (68.0%), neutropenia (61.8%), erythropenia (58.8%), hemoglobin decreased(66.4%), platelets decreased (32.2%), anorexia (45.5%), nausea/vomiting (40.1%), ALT increased(33.5%), pyrexia (32.2%), fatigue (31.2%) and AST increased (30.1%).
b) S-1 therapy
The dosage and administration approved in Japan will be used. That is, “A standard dosage of 80

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mg/m2/day, with a daily dosage of 80 mg/day b.i.d. for a body surface area of <1.25 m2, 100
mg/day b.i.d. for ≥1.25 m2 and <1.5 m2, and 120 mg/day b.i.d. for ≥1.5 m2, to be administeredorally after breakfast and after evening meal. A single course consists of 28 days of administration,
followed by a 14-day rest period. This course is then repeated.”
The antitumor effects obtained in a phase II study conducted in Japan20 were CR in 0 patients,
PR in 19, MR in 4, NC in 17, PD in 18 and NE in 1, with a response rate of 32.2% (19/59 patients).
Adverse drug reactions considered clinically significant that occurred in the 59 patients for whom
adverse drug reactions were evaluable were leukocytopenia (32.2%), neutropenia (27.1%),
hemoglobin decreased (50.8%), platelets decreased (33.9%), AT increased (18.6%), ALT increased(16.9%), anorexia (61.0%), nausea (55.9%), vomiting (35.6%), diarrhea (37.3%), general malaise(47.5%), stomatitis (25.4%) pigmentation (39.0%) and rash (22.0%).
2.4.

Rationale for the study plan

2.4.1. Rationale for the study design
As stated in section 2.2. “Standard treatments for the target disease”, although there is no
standard adjuvant therapy for resected pancreatic cancer, there is a global consensus that such an
adjuvant therapy is necessary. In phase III studies, GEM has been shown to be significantly
superior to 5-FU for the treatment of advanced pancreatic cancer9, with good results as an adjuvant
therapy also reported11-12, gradually affirming its role as a standard treatment. As for S-1, themitigated gastrointestinal toxicity and increased maximum blood concentration of 5-FU provided
by S-1 promise an enhanced antitumor effect, and a high response rate of 32.2% has been reportedwith S-1 in a Japanese phase II study19. Consequently, S-1 is expected to have an equivalent or
better effect compared to GEM as an adjuvant chemotherapy. Oral administration also makes S-1
simpler to implement. This trial positions gemcitabine therapy as a standard adjuvant
chemotherapy for resected pancreatic cancer, and seeks to verify the non-inferiority of S-1 therapy
against gemcitabine therapy in terms of overall survival.
2.4.2. Rationale for selection of evaluation endpoints
2.4.2.1. Primary endpoint
Overall survival is the fundamental objective of postoperative adjuvant chemotherapy, and waschosen as the primary endpoint of this study.
2.4.2.2. Secondary endpoints
Incidence of adverse events, relapse-free survival and HRQOL are possible criteria for
determining whether to select GEM therapy or S-1 therapy in the event of equivalent results interms of the primary endpoint, and were chosen as the secondary endpoints of this study.
2.4.3. Selection of the target population and rationale for selection of assignment adjustment
factors
How target populations and assignment adjustment factors were selected has differed in eachpast and ongoing phase III study, including those mentioned in section 2.2. “Standard treatments
for the target disease”.
・Local residual tumor classification (R): Although opinion is divided on whether R1 patients(residual tumor present upon pathological investigation) are a suitable target for adjuvant
chemotherapy, both R0 and R1 patients have been used in many clinical studies outside of Japan,
and since this study does not include an untreated arm, R1 patients will be included in this study.
There are many reports noting local residual tumor classification as a prognostic factor, and assuch it was chosen as an assignment adjustment factor.
・Histology: Although some studies have included papillary carcinoma and histologies of

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pancreatic cancer (acinar cell carcinoma, cystadenocarcinoma, etc.) other than pancreatic cancer(adenocarcinoma), as these are regarded as separate diseases with different prognoses, this study
will only target invasive ductal carcinoma of the pancreas according to Classification of
Pancreatic Carcinoma 5th edition (excluding cystadenocarcinoma). Accordingly, intraductal
tumor-derived invasive carcinomas are included, but microinvasive carcinomas are not.
・PS: Although many studies include patients with PS from 0-2, due to the likely obstacle PS2
patients would pose to an investigation of the effects of chemotherapy, PS0 and PS1 patientswere chosen as the target of this study.
・Lymph node metastasis (N): This is regarded as a prognostic factor and will be included as an
assignment adjustment factor.
・Study sites: This is a multicenter study, and variables such as patient background, medical
treatment and the like may differ between study sites. Study site has been added as an
assignment adjustment factor.

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2.4.4. Clinical hypothesis and rationale for number of registered patientsA hazard ratio threshold of 1.25 will be used to verify the non-inferiority of the S-1 arm against
the GEM arm in terms of overall survival. Specifically, applying the proportional hazard model,
non-inferiority will be verified if the 95% confidence interval of the S-1 arm to GEM arm death
hazard ratio does not exceed 1.25. The quality-adjusted life year (QALY), which takes HRQOL
into account, will also be calculated and compared between treatment arms. The clinical hypothesisis that the outcome in the S-1 arm is verifiably non-inferior in terms of overall survival andstatistically significantly better in terms of QALY that the GEM arm.
As will be stated in detail in section 13.2 “Scheduled number of registrations and follow-up
period”, with a true S-1 arm to GEM arm hazard ratio of 1/1.15 and a statistical power of 80%, a
total of 240 events (deaths) are required across the treatment arms to verify non-inferiority. The
ongoing progress of a study comparing a GEM arm and observation arm (CONKO-001) reported atthe 2006 ASCO Annual Meeting stated a 3-year survival rate of 36% in the GEM arm and 21% in
an observation arm. Consequently, 36% will be selected as the 3-year survival rate for the GEM
arm (based on the above hypothesis, the anticipated 3-year survival rate in the S-1 arm is 41%). An
exponential distribution was assumed for the survival function, and presuming 360 patients areregistered evenly across both treatment arms during the 3 years, the expected incidence of events at
1 and 2 years after registration is 191 and 237 events, respectively. From the above, with 360
patient registrations, the interim analysis will be performed at 1 year after the end of registration
when there is anticipated to be 180 events, and final analysis will be performed at 2 years after theend of registration. (Upon reporting of the final results of the CONKO-001 study in January 2007
the 3-year survival rate had changed to 34% in the GEM arm and 20.5% in the observation arm.
This drives up the expected incidence of events by only 3%, which was not deemed significant
enough to cause a change in the current study plan.)Note that the results of the above calculations are strongly dependent on the value of the base3-year survival rate (36%) and the exponentiality of the survival distribution. Because ofdifferences in patient selection resulting from the inclusion/exclusion criteria, differences in thepatient population itself, and survival benefits that are expected to result from posttreatment with
S-1 and gemcitabine, the actual number of events may be expected to be fewer than the number
anticipated. Furthermore, it is not definite that registration will proceed as planned. Consequently,
incidence of events will be monitored during and after registration and examined again at bothinterim and final analyses.
2.4.5. Expected patient accrual
A questionnaire survey was sent to each facility planning to participate in the study to discover
the expected annual patient accrual of each study site. The result was a possible overall annual
registration of at least 150 patients. Because this is the first time these a multicenter clinical studyof pancreatic cancer will be conducted in these facilities, the actual number of patients they canregister is likely to be significantly lower than expected. Consequently, the expected number ofregistrations was deemed to be approximately 120 patients/year, or 360 patients registered over 3
years.
2.5.

Summary of anticipated benefits and disadvantages of participation in the study

2.5.1. Anticipated benefits
The drugs used in this study (gemcitabine and S-1) are approved for health insurance coverageand the treatment methods employed in this study are performed as normal medical practicecovered by health insurance. In addition, because all medical treatment costs, including drug costs,
incurred during the study period will either be borne by patients’ health insurance or as
out-of-pocket payments, participation in this study will provide the participant with no special
medical or financial benefit compared to normal medical treatment.
2.5.2. Anticipated risks and disadvantages

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The main adverse events participants are likely to experience are those cited in section 2.3.2. ofthis protocol. Treatment will be provided within the dose ranges printed in the package inserts for
gemcitabine and S-1, and appropriate supportive therapy (preventive administration of antiemetics,
G-CSF, etc.) provided if adverse events are observed. Upon observation of a serious adverse event,utmost effort will be taken to enact safety measures including prompt examination of the entire
treatment arm and informing the Efficacy and Safety Evaluation Committee.
In order to minimize the potential risks and disadvantages of adverse events, matters such as
patient selection criteria, criteria for treatment change and concomitant therapy/supportive therapy
will be examined carefully within each treatment arm. Costs associated with the treatment of injury
to health caused by this clinical study will, as a general rule, be borne by the patient or be subject tohealth insurance coverage if applicable.
2.6.

Significance of this study

With reporting of the final results of CONKO-001 a global consensus was reached on the use of
gemcitabine as an adjuvant therapy, while the use of gemcitabine as adjuvant therapy is spreadingin general medical practice in Japan. Meanwhile, in a Japanese phase II study a high response rate
has been reported for S-1 therapy. S-1 is an oral drug that is easy to administer that has an efficacy
anticipated to be equivalent to or better than gemcitabine. S-1 is believed to be clinically significant
enough to deserve further elucidation of the results of this phase II study.
2.7.

Ancillary research

No ancillary research is planned for the start of this study (April 2007). Any ancillary researchundertaken after the start of this study will be conducted according to the provisions below.
(1) Ancillary research that uses only data obtained in the course of this study in full or in part (adata package where personal information on registered patients is masked) will be conducted
after the preparation of a separate study protocol and subsequent approval by the Steering
Committee and Efficacy and Safety Evaluation Committee.
(2) Ancillary research that adds new personal information on registered patients to all or some ofthe data obtained in the course of this study (genetic analysis, etc.) will be conducted after the
preparation of a separate study protocol and subsequent approval by the Ethics Review Board(ERB) of each participating study site.

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3. Standards and definitions used in this study
The histology of pancreatic cancers will be classified according to Classification of Pancreatic
Carcinoma 5th edition21, and histopathological staging and regional lymph node definitions will
follow the UICC 6th edition22.
3.1.

Histology classification*: Targets of this study are underlined.
(1) Epithelial tumors
A. Exocrine tumors
1. Serous cystic tumors a) Serous cystadenomab) Serous cystadenocarcinoma
2. Mucinous cystic tumorsa) Mucinous cystadenomab) Mucinous cystadenocarcinoma
3. Intraductal tumors

1) Intraductal papillary-mucinous tumorsa) Intraductal papillary-mucinous adenomab) Intraductal papillary-mucinous carcinoma
2) Intraductal tubular tumora) Intraductal tubular adenomab) Intraductal tubular carcinoma

4. Atypical hyperplasia and carcinoma in situ
5. Invasive ductal carcinomaa) Papillary adenocarcinomab) Tubular adenocarcinomac) Adenosquamous carcinomad) Mucinous carcinomae) Anaplastic carcinomaf) Invasive mucinous cystadenocarcinomag) Intraductal tumor-derived invasive carcinoma
6. Acinar cell tumorsa） Acinar cell adenomab） Acinar cell adenocarcinoma

B. Endocrine tumors
C. Combined tumors
D. Epithelial tumors of uncertain differentiationa) Solid-pseudopapillary tumorb) Pancreatoblastomac) Undifferentiated carcinoma
E. Unclassifiable
F. Others(2) Nonepithelial tumors
Hemangioma
Lymphangioma
Leiomyosarcoma
Malignant fibrous histiocytoma
Malignant lymphoma
Paraganglioma
Others3.2.

Cancer staging

The below cancer staging of the UICC 6th edition will be used.

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N0
M0

Tis

0

T1
T2
T3
T4

IA
IB
IIA
III
IV

M1

N1

IIB
IIB
IIB
III
IV

1) Local tumor
Tis: Carcinoma in situ
T1: Tumor limited to pancreas, 2 cm or less in greatest dimension
T2: Tumor limited to pancreas, more than 2 cm in greatest dimension
T3: Tumor extends beyond pancreas, but without involvement of celiac axis or superior
mesenteric artery
T4: Tumor involves celiac axis or superior mesenteric artery
2) Lymph node metastasis
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
3) Distant metastasis
M0: No distant metastasis
M1: Distant metastasis
3.3.

Regional lymph nodes

The definition of regional lymph nodes in the UICC 6th edition22 will be used. These definitions
are equivalent to the lymph node numbers of the Classification of Pancreatic Carcinoma 5th edition
as shown below.

Superior:
Inferior:
Anterior:

Posterior:

UICC 6th edition Classification of Pancreatic Carcinoma 5th edition
Superior to pancreatic head
17a, 13a, 12a, 12b, 12p, 12h,
Superior to pancreatic body
8a, 8p, 11p
Inferior to pancreatic head17b, 13b
Inferior to pancreatic body18
Anterior pancreaticoduodenal,
17a, 17bpyloris (for tumors of head only), and 5, 6
proximal superior mesenteric artery
14p, 14d
Posterior pancreaticoduodenal,
13a, 13b
common bile duct, and12b
proximal superior mesenteric artery
14p, 14d

Splenic：

Hilum of spleen and tail of pancreas
10, 11d(for tumors of body and tail only)
Celiac artery：(for tumors of head only)
9*, 7*: Because the target of this study is patients with stage II or lower, or stage III where resection
included the celiac artery according to the UICC 6th edition22 staging system, lymph nodemetastases will include regional lymph nodes. Consequently, the lesions below are judged tobe distant metastases and not targets of the study. However, though #9 is a pancreaticbody-tail lesion, it was judged appropriate to include it among regional lymph nodes and it
shall not be considered a distant metastasis.
Distant metastatic lymph nodes
Pancreatic head lesion: 10, 11d, 15, 16
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5, 6, 7, 15, 16
Pancreatic lesion: 15, 16

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4. Patient selection criteria
4.1.

Eligibility criteria (enrolment criteria)

1) Patients with a resected pancreatic cancer that was a histologically verified invasive ductal
carcinoma of the pancreas (based on Classification of Pancreatic Carcinoma 5th edition21,
excluding cystadenocarcinoma)
2) Patients with a macroscopic total resection of the primary tumor, and residual primary tumor
that satisfies all of the items below according to the UICC 6th edition22 histopathologic staging
system・Stage II or lower, or stage III where resection included the celiac artery・Local residual tumor classified as R0 or R1・Cytologic examination negative upon intraoperative peritoneal lavage
3) Absence of distant metastases and malignant ascites
4) Adequate oral intake is possible5) Age of 20 years or above
6) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
7) Absence of chemotherapy or radiotherapy within past 3 years8) Within 10 weeks following resection of pancreatic cancer
9) Major organ functions adequately conserved as shown below (bone marrow, lungs, kidneys)
Satisfies all the criteria below in measurements taken from 7 days prior to registration.
・White blood cell count: ≥3,000/mm3, ≤12,000/mm3
・Platelet count: ≥100,000/mm3
・Hemoglobin: ≥8.0 g/dL
・Total bilirubin: ≤2.0 mg/dL
・AST and ALT: ≤100 IU/L・Serum creatinine: ≤1.2 mg/dL
10) Written informed consent given

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4.2.

Exclusion criteria

1) Patient has been treated with gemcitabine or S-1
2) Recurrence confirmed upon investigations conducted prior to registration*Cases where the tumor marker has not fully declined or where only mild ascites is observed
upon CT are not deemed recurrence.
3) Moderate or more severe pleural effusion or ascites upon chest X-ray and abdominal CT
4) Pulmonary fibrosis or interstitial pneumonia clearly observed in plain chest X-ray findings5) Inadequately controlled watery diarrhea*Whether a patient has diarrhea 4 or more times a day while receiving adequate supportive
therapy will be used as the indicator to determine whether watery diarrhea is inadequately
controlled.
6) Heart failure of Class III (Marked limitation of physical activity. Comfortable at rest, bust lessthan ordinary activity causes fatigue, palpitation, or dyspnea.) or Class IV (Unable to carry out
any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any
physical activity is undertaken, discomfort is increased.) according to the New York Heart
Association functional classification
7) Myocardial infarction within 6 months following onset of pancreatic cancer
8) An active infectious disease (pyrexia of 38°C or higher, etc.) (excluding viral hepatitis)
9) Inadequately controlled diabetes mellitus*Fasting blood sugar ≥200 mg/dl, HbA1c ≥10.0, etc. will be used by investigators as
indicators to determine whether diabetes mellitus is inadequately controlled. HbA1c
measurements are not required if a judgment can be made using fasting and postprandial
blood sugar measurement.
10) Blood transfusion required within 2 weeks prior to registration
11) Other serious complications (heart failure, kidney failure, liver failure, active peptic ulcer,
paresis of intestine, etc.)
12) Participation in the study by the patient is judged difficult due to a complicating psychiatricdisorder or psychological symptoms
13) Serious drug allergy14) Active multiple primary cancers (synchronous multiple primary cancer or within 3 years of adisease-free period following unsynchronous multiple primary cancer)
15) Pregnant or breast feeding woman, woman of childbearing potential, or woman who is willing
to bear children or desires to bear children16) Man who is willing to conceive a child17) Using flucytosine, phenytoin or warfarin potassium18) An investigator judges participation to be incompatible with the safe conduct of the study

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5. Registration and assignment
5.1.

Registration procedure

Target patients will be confirmed to satisfy all eligibility criteria and no exclusion criteria, andafter completing all required sections of a case report from (CRF), the CRF will be sent by fax to
the CSPOR data center.
Contact details and reception times for patient registration
CSPOR data center (within NPO Japan Clinical Research Support Unit)
Tel
03-3254-8029
Fax
03-5298-8536
Weekdays: 10am-5pm(Not open on national holidays, weekends and from December 29 to January
3)
Contact relating to patient selection criteria
Study administrator
Akira Fukutomi
Chief Physician, Department of Gastrointestinal Medicine, Shizuoka Cancer
Center1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777
Tel
055-989-5222
Fax
055-989-5634
E-mail a.fukutomi@scchr.jp
5.1.1. Notes on registration
1) Registration after commencement of protocol treatment is not permitted in any circumstance.
2) Registration will not be acknowledged until all details/necessary sections of the CRF have been
completed.
3) The CSPOR data center will confirm patient eligibility, and after assigning an eligible patient
to a treatment arm based on the assignment adjustment factors in section 5.2. of this protocol,
will issue a registration number and a Registration Confirmation Form (RCF).
4) The CSPOR data center will fax the RCF to the fax number of the investigator noted in the
CRF. Patients will be deemed registered by the sending of this RCF. RCFs will be retained byeach study site.
5) Excluding cases of patient withdrawal of consent that include refusing the use of data forresearch, once registered, patient registration will not be reversed (deleted from the database).
In the event of registration duplication, the antecedent registration information (registration
number) will be used.
6) Discovery of registrations made in error or duplicate registrations will be promptly reported to
the CSPOR data center.
7) Study sites will be responsible for calculating body surface area and drug dose. (See protocol
section 6.1.2.)
5.2.

Random assignment and assignment adjustment factors

Upon registration, patients will be randomly assigned to a treatment arm by the CSPOR data
center.
During random assignment, to prevent any major imbalance between treatment arms theminimization method will be employed using (1) R(0 vs.1), (2) N(0 vs. 1) and (3) study site as
adjustment factors. Detailed procedures on the random assignment method used will not be
disclosed to researchers at participating study sites.

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5.3.

Reporting of registration confirmation and the pre-treatment report

Investigators will confirm patient registration by receipt of the RCF sent by fax from the CSPOR
data center. Data management in this study will be performed using an electronic data capture(EDC) system using the PDF file format (the system will be sent by post to participating study sites
on removable USB drives). After confirming patient registration, an investigator or clinicalresearch coordinator (CRC) will simultaneously insert into a PC a USB drive containing the EDC
system and a USB drive to be used for backup (both sent by the CSPOR data center), start the EDC
system, open the CRF (in PDF file format) from the opened browser, and enter the registration
number together with the necessary data into the pre-treatment report for the registered, eligible
patient. After that, the investigator or CRC will promptly copy the CRF (the pre-treatment report
into which the necessary data has been entered that is in PDF file format) from the backup USB
drive to another USB drive that is to be used for data submission, and post the data submission
USB drive to the CSPOR data center by a prescribed method.
A patient’s pre-treatment report will be posted to the CSPOR data center in the same way even if
treatment is not started within 15 days of registration and assignment as prescribed.

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6. Treatment plan and treatment change criteria
Treatment and changes to treatment will be implemented as described in this section, unless such
implementation threatens the safety of the patient.
In cases where following the protocol is judged medically dangerous, treatment changes will be
implemented according to the medical judgment of the investigator. These are protocol deviations,but will be regarded as medically appropriate deviations. (See protocol section 14.1.2 “Protocol
deviations and violations”.)
6.1.

Protocol treatment

Protocol treatment will be started within 15 days of registration.
If treatment is not started within 15 days of registration for a particular reason, that reason will
be entered into a records form (comments section of the progress report). If it has been decided thattreatment cannot be started, the details of this decision will be entered into the treatment end reportas “Protocol treatment discontinued”.
6.1.1. Drugs useda) Gemcitabine (Ely Lilly: Gemzar®)
200 mg/Vial, 1 g/Vial 200mg、1g/Vial
200 mg/Vial and 1 g/Vial preparations will be used after dilution in at least 5 ml and 25 ml ofphysiological saline, respectively.
b) S-1 (Taiho Pharmaceutical: TS-1®)
20 mg/capsule, 25 mg/capsule
Postprandial oral administration, b.i.d.
6.1.2. Administration method
Study sites will be responsible for calculating body surface area and drug dose. Dose corrections
made to address changes in body weight after starting treatment will be left to the judgment of eachstudy site.
a) Gemcitabine therapy
・ 1,000 mg/m2 administered by 30-minute intravenous infusion. (Dose calculated according tobody surface area, rounded off to the nearest 100 mg/body.)
・ Administered once weekly for 3 weeks, followed by a 1-week rest period.
・ Once course lasts 4 weeks and is repeated.
b) S-1 therapy
・ 80 mg/m2/day (see initial doses below) b.i.d., taken after breakfast and evening meal.
・ Administered daily for 28 days, followed by a 14-day rest period.
・ One course lasts 6 weeks and is repeated.
S-1 initial doses
Body surface area
2

<1.25m≥1.25m2, <1.5m2≥1.5m2S-1 initial dose

Morning/Noon/Evening

80 mg (20 mg cap ×4)/day
100 mg (25 mg cap ×4)/day
120 mg (20 mg cap ×6)/day

2–0-2
2–0-2
3–0-3

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6.2.

Criteria for protocol treatment completion and discontinuation

6.2.1. Definition of protocol treatment completiona) Gemcitabine (Eli Lilly: Gemzar®)・ Gemcitabine therapy is completed after 6 months. Specifically, the course ongoing at 6 months
after starting gemcitabine therapy will be the final course. (A new course will not be started
after 6 months has passed.)b) S-1 (Toho Pharmaceutical: TS-1®)
・ S-1 therapy is completed after 4 courses.
6.2.2. Criteria for discontinuation of protocol treatment
Adjuvant chemotherapy will be discontinued if any of the below conditions is met.
1) Recurrence is confirmed by diagnostic imaging that includes CT, or recurrence is determinedclinicallyNote)2) For gemcitabine therapy, administration could not be started by 28 days after the final
administration date3) For gemcitabine therapy, toxicity that meets criteria for dose reduction occurs after the dose has
already been reduced to Level 2 after criteria for dose reduction were met4) For S-1 therapy, administration could not be started by 14 days after the scheduled course startdate5) For S-1 therapy, toxicity that meets criteria for dose reduction occurs after the dose has alreadybeen reduced to Level 1 after criteria for dose reduction were met6) An adverse event that can cause serious sequela, such as interstitial pneumonia
7) Continuation of medical examinations has become problematic due to patient circumstancessuch as moving house, change of physician, being too busy, etc.
8) Patient requests to discontinue protocol treatment
9) Other cases an investigator finds discontinuation necessary
Note)・ Recurrence will not be diagnosed based on changed symptoms or an increase in tumor markers
only. A diagnosis of recurrence requires imaged findings to support the diagnosis.
・ As shown below, recurrence will not be diagnosed if doubts remain regarding the imaged
findings. Detailed examination will be conducted by further diagnostic imaging or follow-up
observation.
Tiny hepatic lesion upon CT, etc.
Difficult to differentiate between metastases to liverand liver abscess
Lymph nodes enlarged
Difficult to differentiate between metastases to lymph
nodes and inflammatory adenopathy
Increase of a local soft-tissue mass
Difficult to differentiate between local recurrence andinflammation-induced scarring
Ascites
Difficult to differentiate between peritoneal nodules
and carcinomatous peritonitis not accompanied by mesenteric thickening

・ The date of recurrence will be date a definite diagnosis of recurrence was made. The date ofrecurrence will not be changed retroactively upon reexamination of imaged findings, etc.

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6.3.

Treatment change criteria

The following terminology will be used with respect to change criteria. (Common to both
treatment arms.)
Discontinuation: End of ongoing protocol treatment. No possibility of restarting treatment.
Postponement: Delay of the start of a treatment course or of administration of a study drug
past the scheduled date.
Dose interruption: Temporary stoppage of treatment, with the possibility of restarting
treatment during an ongoing course.
Dose suspension: Temporary stoppage of treatment, with no possibility of restarting
treatment during an ongoing course but a possibility of restarting protocol treatment
continuing on from the following course.
Skip: Proceeding to the next administration schedule without giving treatment.

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6.3.1. Arm A: Treatment change criteria for gemcitabine therapy
6.3.1.1. Course start criteria
The first dose of each treatment course will be started from the scheduled start date or the day
before the scheduled start date, after all of the below-described course start criteria have beensatisfied. If any of the course start criteria are not satisfied, course start (the first dose) will bedelayed by increments of 1 day to 1 week.
If administration is not started by 28 days after the date of final administration, the protocoltreatment will be discontinued.
If the third dose of a course (day 15) is skipped, day 22 (±2 days) will become the scheduledstart date of the next course of treatment (day 1 of the next course).
Course start criteria for gemcitabine therapy
1） White blood cell count: ≥3,000/mm32） Platelet count: ≥100,000/mm3
3） Hemoglobin: ≥6.5 g/dL4） Total bilirubin ≤3 mg/dL
5） AST (GOT): ≤150 IU/L
6） AST(GPT): ≤150 IU/L
7） No pyrexia of 38°C or above
8） No inadequately controlled diarrhea
9） No other non-hematological toxicity of Grade 2 or greater for which an investigator
judges administration inappropriate
6.3.1.2. Criteria for skipping second (day 8) or third (day 15)
The second dose (day 8) or third dose (day 15) to be given on the scheduled date ofadministration or the day before the scheduled date of administration will be skipped if any of theadverse events shown below in “Criteria for skipping second (day 8) or third (day 15) dose” isobserved.
Criteria for skipping second (day 8) or third (day 15) dose
1） White blood cell count: <2,000/mm32） Platelet count: <70,000/mm33） Total bilirubin: >3 mg/dL
4） AST(GOT): >150 IU/L
5） ALT(GPT): >150 IU/L
6） Pyrexia of 38°C or above7） Development of inadequately controlled diarrhea
8） Another non-hematological toxicity of Grade 2 or greater for which an investigator
judges administration inappropriate* The date of the second (day 8) and third (day 15) administrations may be changed by ±2 days.
A minimum of 5 days interval will be provided after the previous administration.
* If a long period of national holiday or the like does not allow administration even when theabove-allowed changes to the date of administration are applied, administration will be delayed
by a maximum of 7 days. In the event of such a delay, the next administration date will bedecided as shown below.
Delay of second administration → Third administration performed 7 days after (±2days)
Delay of third administration →First administration
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6.3.1.3. Criteria for dose reduction
If any of the below dose reduction criteria is met, the dose level of the next administration will
be reduced by one level. The dose will be reduced by a single level irrespective of whether 2 ormore of the below dose reduction criteria is met. The dose will not be increased once the dose has
been reduced. If criteria are met for dose reduction after the dose has already been reduced to level-2, protocol treatment will be discontinued.
Dose levels
Drug

Dose level

GEM Level 1 (all)Dose1000 mg/m2/day
2First (day 1), second (day 8), third (day 15)

Level -1 (minus 1)

800 mg/m /dayFirst (day 1), second (day 8), third (day 15)

Level -2 (minus 2)

600 mg/m2/day

First (day 1), second (day 8), third (day 15)

Gemcitabine therapy dose reduction criteria
1） White blood cell count <1,000/mm32） Platelet count <25,000/mm33） Platelet transfusion required*
4） Second (day 8) administration skipped
5） Third (day 15) administration skipped, AND unable to start next course on day 22(±2 days)6） Unable to start administration within 14 days after the date of final administration*: Satisfaction of this criterion will not be based on whether a platelet transfusion is
actually performed, but based on the clinical judgement as to whether a platelettransfusion should be performed.
6.3.1.4. Schedule change
If the normal course of 3-week administration and 1-week rest is changed to a course of 2-weekadministration and 1-week rest on two consecutive courses due to a skipped dose, later courses may
be administered using the 2-week administration and 1-week rest schedule. However, if criteria arethen satisfied for dose reduction, in addition to reducing the dose level the treatment course will be
returned to 3-week administration and 1-week rest.

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6.3.2. Arm B: Treatment change criteria for S-1 therapy
6.3.2.1. Course start criteria
The first dose of each treatment course will be started from the scheduled start date or the day
before the scheduled start date, after all of the below-described course start criteria have beensatisfied. If any of the course start criteria are not satisfied, course start (the first dose) will bedelayed by increments of 1 day to 1 week.
If administration is not started by 14 days after the date of final administration, the protocoltreatment will be discontinued.
If the period of administration of the previous course has been delayed due to dose interruption,
the next course may be started within 2 weeks of the date of final administration of the previous
course, providing all the course start criteria have been satisfied.
After dose suspension in the previous course, the next course may be started within 6 weeks ofthe previous course providing all the course start criteria have been satisfied.
There will be an interval of at least 1 week between the date of final administration of theprevious course and the start of the next course.
Course start criteria for S-1 therapy
1） White blood cell count: ≥3,000/mm32） Platelet count: ≥100,000/mm3
3） Hemoglobin: ≥6.5 g/dL4） Total bilirubin: ≤3 mg/dL
5） AST (GOT): ≤150 IU/L
6） ALT (GPT): ≤150 IU/L
7） Serum creatinine: ≤1.5 mg/dL
8） No pyrexia of 38°C or above
9） No inadequately controlled diarrhea
10）No other non-hematological toxicity of Grade 2 or greater where an investigator
judges administration to be innapropriate

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6.3.2.2. Dose interruption criteria
Study drug administration will be interrupted if any of the below adverse events is observed.
S-1 therapy dose interruption criteria
1） White blood cell count: <2,000/mm32） Platelet count: <50,000/mm33） Total bilirubin: >3 mg/dL
4） AST (GOT): >150 IU/L
5） ALT (GPT): >150 IU/L
6） Serum creatinine: >1.5 mg/dL
7） Pyrexia of 38°C or above8） Development of inadequately controlled diarrhea
9） Another non-hematological toxicity of Grade 2 or greater an investigator judges
requires dose interruption
Note・ Dose interruptions will not be implemented by the judgment of the patient herself/himself. Make
sure that patients always contact the investigator or an agent of the investigator for instructions
first.
・ If a patient does not take the study drug for any reason other than those described above, such as
forgetting to take a drug or deciding not to take the drug, this will not be regarded as a doseinterruption (to be handled as ongoing continued treatment).
・ When a dose interruption enacted by the judgment of the patient herself/himself is identified thatsatisfies any of the above dose interruption criteria, it will be regarded as a dose interruption.
・ Although hospital visits normally occur every 2 weeks, after a dose interruption the onset ofadverse events will be checked within 8 days of interrupting the dose, if possible.
・ It is desirable to check for adverse events once weekly during the first course of treatment.

6.3.2.3. Criteria for restarting treatment after dose interruption
After a first dose interruption, administration will be promptly restarted if all the criteria below
are satisfied.
A second dose interruption will be treated as a dose suspension, upon which administration will
not be performed within the same course (see criteria for dose suspension).
Administration will be continued even after a restart of treatment occurring after day 28. The
treatment that was to be given within the 28-day course of treatment will be completed.
Criteria for restarting treatment after dose interruption for S-1 therapy
1） White blood cell count: ≥2,800/mm32） Platelet count: ≥70,000/mm33） Total bilirubin: ≤1.5 mg/dL
4） AST (GOT): ≤150 IU/L
5） ALT (GPT)： ≤150 IU/L
6） Serum creatinine: ≤1.5 mg/dL
7） No pyrexia of 38°C or above
8） No inadequately controlled diarrhea
9） All non-hematological toxicities that became the reason for dose interruption
improved to Grade 1 or below

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6.3.2.4. Dose suspension criteria
If any of the adverse events below are observed all further administration will be suspended forthe ongoing course of treatment.
Dose suspension criteria for S-1 therapy
1） White blood cell count: <1,000/mm32） Platelet count: >25,000/mm33） Platelet transfusion required*4） Hemoglobin: <6.5 g/dL
5） Non-hematological toxicity of Grade 3 or above
6） Neurological disorder, such as leukoencephalopathy, of Grade 2 or above7） After dose interruption, no improvement to satisfy criteria for restarting
administration within 15 days
8） Dose interruption neded twice within a single course due to adverse events*： Satisfaction of this criterion will not be based on whether a platelet transfusion is
actually performed, but based on the clinical judgement as to whether a platelettransfusion should be performed.
Note・ If an adverse event does not improve within 8 days of dose suspension, the adverse event will bechecked again within 15 days for its improvement, continuation or exacerbation.
・ After dose suspension, the next course of treatment will be started with a reduced dose (seesection 6.3.2.5.).

28日分投与終了
休薬
次コース開始規準
次コース
休薬規準

End of 28 days of administration
Dose interruption
Criteria for starting next course met
Next course
Dose interruption criteria met

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再開規準
再開
15日以上休薬後も再開規準を満たさず
休止
次コース開始規準、減量後再開
コース内2回目休薬規準=休止
休止規準
S-1投与
*:1週間以上の休薬または休止が必要

Criteria for restarting treatment met
Restart
Criteria for restart not satisfied within 15
days of dose interruption
Dose suspension
Criteria for starting next course met, restart
after dose reduction
Criteria for dose interruption met for second
time within single course = dose suspension
Dose suspension criteria met
S-1 administration*: Dose interruption for 1 week or more, ordose suspension required

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6.3.2.5. Dose reduction criteria
After dose suspension, the next course of treatment will be reduced to dose level -1. There will
be no dose increase after a dose reduction. If a criterion for dose suspension is satisfied again after
a reduction to level -1, the protocol treatment will be discontinued.
Dose level
Drug

Dose level

Dose

S-1

Level 0 (all doses)

120 mg/body/day↓
100 mg/body/day

Level -1 (minus 1)

100 mg/body/day↓
80 mg/body/day

Breakdown of doses after dose reduction
Body surface area
Dose after S-1 dose reduction<1.25m2≥1.25m2, <1.5m2≥1.5m250mg (25 mg cap ×2)/day
80mg (20 mg cap ×4)/day
100mg (25 mg cap ×4)/day

80 mg/body/day↓
50 mg/body/day

Morning/Noon/Evening
1–0-1
2–0-2
2–0-2

6.3.3. Consultations related to treatment changes
Please contact section 16.2. “Study administrators” if there are any questions regarding changes
to treatment.
Study administrator contact: Akira Fukutomi
Department of Gastrointestinal Medicine, Shizuoka Cancer Center
1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777
Tel
055-989-5222
Fax
055-989-5634
E-maila.fukutomi@scchr.jp

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6.4.

Concomitant therapies/Supportive therapies

6.4.1. Recommended and non-recommended concomitant therapies and supportive therapies
The below are recommended concomitant/supportive therapies. Non-implementation of these
therapies will not be regarded as a protocol deviation.
(1) G-CSF
G-CSF will be administered in accordance with its coverage under health insurance as shown in
the table below. G-CSF will not be administered preventively.
・When pyrexia (as a general rule, 38°C or higher) is observed with aneutrophil count of <1000/mm3
Timing of start ・When a neutrophil count of 500/mm3 is observedof treatment
・If, during the previous course, pyrexia (as a general rule, 38°C or higher) anda neutrophil count of <1000/mm3 or if a neutrophil count of 500/mm3 wereobserved, when a neutrophil count of <1000/mm3 is observed afteradministering the same chemotherapy
Dosage and・Filgrastim: Subcutaneous injection of 50 μg/m2 q.d.
administration ・Nartograstim: Subcutaneous injection of 1 μg/kg q.d.
・Lenograstim: Subcutaneous injection of 2 μg/kg q.d.
・Administration will be stopped when the neutrophil count reaches 5000/mm3
or greater after reaching its lowest value.
Timing of・Stopping or reducing the dose will be reviewed if the neutrophil countdiscontinuation recovers to 2000/mm3 or greater, there are no symptoms that cause suspicionof an infectious disease, AND it has been judged that the safety of the patient
can be assured in terms of her/his reaction to the drug.
(2) Treatment for pyrexia during a decreased neutrophil count1) If a patient experiences pyrexia of 38°C or higher while having a decreased neutrophil count(neutrophil count ≤1,000/mm3) (febrile neutropenia), excluding cases when the pyrexia isjudged clinically to be clearly unrelated to an infection, the patient will be regarded as having
infection as a complication and antibiotic treatment will promptly be started together withmicrobiological investigations, such as blood cultures.
2) In the event of febrile neutropenia with a relatively severely decreased neutrophil count(neutrophil count ≤500/mm3, or neutrophil count ≤1,000/mm3 that is expected to further
decrease to ≤500/mm3), as a general rule, broad-spectrum antibiotics (third- or a higher
generation of cephems, carbapenems, etc.) will be given by intravenous administration.
3) Antibiotics will be selected (drug and multi-drug therapy or monotherapy) by a risk judgment
based on the neutrophil count (in particular, whether the neutrophil count is ≤100/mm3) andmonocyte count, period of sustained decreased neutrophil count, whether the neutrophil countis expected to increase, presence of mucous membrane disorders, the situation at the study sitewith regards to drug-resistant bacteria, previous history of infection and the like. Multi-drugtherapies will, as a general rule, consist of concomitant use of a β-lactam antibiotic and an
aminoglycoside.
4) Whether vancomycin will be used from the start of such treatment will be decided based on thegeneral condition of the patient, the patient’s existing normal bacterial flora and the situation in
the study site with regards to MRSA.
5) The results of blood cultures, etc., the progress of symptoms, the results of investigations tofind the infection focus and the like will be reassessed within 3-5 days after starting antibiotics.
The arbitrary administration of antibiotics will be avoided, with the antibiotics administered to
be changed if pyrexia is not alleviated within 3 days of starting treatment, or if the pathogen is
identified.
6) Although the use of cytokine preparations such as G-CSF can fall under coverage offered byhealth insurance, their efficacy in the treatment of infections will not be overestimated. It will

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be taken into account that G-CSF is, in particular, slow to have an effect on severe/early onset
decreased neutrophil counts.
Note) IDSA guidelines (Clinical Infectious Disease 34: 730-751, 2002), etc. will be referenced withrespect to the details of antibiotic selection, methods of risk assessment, duration of antibiotic
administration and the like.

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6.4.2. Permitted concomitant therapies/supportive therapies
1) Selective 5-HT3 receptor antagonists, metoclopramide, steroids, etc. may be used as
appropriate to prevent the exacerbation of nausea/vomiting and anorexia, including forpreventive use.
2) Steroidal drugs may be used as necessary for fatigue, anorexia and emaciation.
3) Therapeutic drugs for complications such as hypertension and symptomatic medications suchas morphine may be used concomitantly as long as they do not interact with the anticancer
drugs being used.
6.4.3. Non-permitted concomitant therapies/supportive therapies
1) While protocol treatment is ongoing, anticancer drugs other than those included in the protocoltreatment regimen, radiotherapies, hormone therapies other than steroids, and immunotherapies
will not be used. (The use of so-called folk remedies and the like will be avoided as possible,
though their use according to the wishes of the patient will be left to the judgment of theinvestigator.)2) G-CSF preparations will not be administered preventively.
3) Use of flucytosine, phenytoin and warfarin potassium, which are contraindicated forconcomitant use or precautioned against for concomitant use with S-1, will be prohibited
during the administration period of this study.
6.5.

Posttreatment

No posttreatment will be given after the end of protocol treatment or after discontinuation unlessrecurrence is observed. Details will not be prescribed in advance with respect to the posttreatment
to be given upon confirmation of recurrence. However, because recurrences during protocoltreatment or within 6 months of completion of protocol treatment will be identified as cases ofunresponsiveness to the protocol treatment, the below crossover treatments will be recommended.
Recurrence during protocol treatment or within 6 months after completion of protocoltreatment (recommended)
Protocol treatment

Treatment after recurrence

Arm A: Gemcitabine therapy→

S-1 therapy

Arm B: S-1 therapy→

Gemcitabine therapy

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7. Drug information and anticipated adverse reactions
7.1.

Drug information

This section includes important information on drugs used in this study. Package inserts for the
drugs will also be included at the end of the protocol.
7.1.1. Gemcitabine HCl (GEM)
Product name: Gemzar Injection (Eli Lilly Japan K.K.), 200 mg/Vial, 1 g/Vial
Mechanism of action
Gemcitabine (dFdC) is metabolized intracellularly to the active diphosphate (dFdCDP) andtriphosphate (dFdCTP) nucleosides. These exhibit cytocidal action by direct and indirect
inhibition of DNA synthesis. dFdCTP inhibits DNA synthesis directly by competing withdeoxycytidine triphosphate (dCTP) for incorporation into the DNA chain, after which it
induces cell death (apoptosis). dFdCDP inhibits DNA synthesis indirectly by inhibiting
ribonucleotide reductase, which reduces the intracellular concentration of dCTP, indirectly
enhancing inhibition of DNA synthesis.
Indications
Non-small cell lung cancer, pancreatic cancer, and biliary cancer
Dosage and administration
In adults, normally one dose of 1000 mg/m2 is given by 30-minute intravenous infusion. One
dose is given once weekly for 3 weeks, followed by a 1-week rest period. One course lasts 4
weeks and is repeated.
Note that the dose will be reduced as appropriate according to age, symptoms or onset ofadverse drug reactions.
Main pharmacokinetics
After five patients with advanced cancer were given a 1000 mg/m2 intravenous infusion of
14
C-gemcitabine hydrochloride, 92-98% of radioactivity was recovered in patient urine/feces
over the following 7 days. Since more than 99% of this radioactivity was recovered in urine,
the main excretion pathway for gemcitabine was concluded to be in urine.
Main adverse drug reactions
Circulatory 1 to <10%: Tachycardia, blood pressure increased<1%: Blood pressure decreased, anginal pain, palpitations, ventricular
extrasystoles, paroxysmal supraventricular tachycardia, abnormal ECG (STelevation), blood pressure increased
Respiratory ≥10% or incidence unknown: Hypoxemia
1 to <10%: Dyspnea, hypercapnia<1%: PIE (pulmonary infiltration with eosinophilia) syndrome, wheezing,
cough, expectoration, shortness of breath
Renal≥10% or incidence unknown: Total protein decreased, electrolyte abnormality
1 to <10%: Albumin decreased, BUN increased, proteinuria, hematuria,
creatinine increased<1%: Oliguria
Gastrointestinal≥10% or incidence unknown: Anorexia, nausea/vomiting
1 to <10%: Diarrhea, constipation, stomatitis<1%: Stomach discomfort, gingivitis
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1 to <10%: Bilirubin increased, A/G ratio decreased<1%: Urobilinuria
Neuropsychiatric
1 to <10%: Headache, dizziness<1%: Paresthesia, sleep loss, lethargy, numbness
Dermatologic ≥10% or incidence unknown: Rash, urticaria<1%: Alopecia, pruritis
Injection site ≥10% or incidence unknown: Injection site reaction (phlebitis, pain, erythema)
Vascular≥10% or incidence unknown: Peripheral vasculitis, peripheral gangrene
Other≥10% or incidence unknown: Fatigue, malaise, asthenia, pyrexia, edema, flu
like symptoms (malaise, asthenia, pyrexia, headache, chills, myalgia, sweaty,rhinitis, etc.), CRP increased, radiation recall reaction
1 to <10%: Platelets increased, weight decreased, urine sugar positive,
eosinophilia<1%: Weight increased, arthralgia, pain, chills, bleeding of ocular fundus, bodytemperature decreased, hot flush, tinnitus, eye discharge, chest discomfort,dysgeusia, epistaxis
Severe adverse drug reactions (important adverse drug reactions)
The incidences stated below were observed in domestic (Japanese) clinical studies.
1. Bone marrow depression
Because white blood cells decreased (68.0%, 13.0% decreased to <2000/μL), nutrophils
decreased (61.8%, 24.5% decreased to <1000/μL), platelets decreased (32.2%, 4.6%
decreased to <50,000/ μL), anemia [hemoglobin decreased (66.4%, 15.4% decreased to <8.0g/dL), red blood cell decrease (58.8%)], etc. have occurred, hematology tests should be
conducted frequently, and appropriate action taken such as dose reduction or dose interruption
if an abnormal measurement is observed. Note that cases of death caused by sepsis that may
be due to severe white blood cells decreased have been reported.
2. Interstitial pneumonia (1.4%)
Because interstitial pneumonia has occurred, patients should be observed carefully including
by chest X-ray exams, and if an abnormality is observed administration should be
discontinued and appropriate treatment given. Note that cases of death have been reported that
may have been caused by interstitial pneumonia.
3. Anaphylactoid symptoms (0.3%)
Because anaphylactoid symptoms including dyspnea have occurred, if any of such symptoms
develop administration should be discontinued and appropriate treatment given.
4. Myocardial infarction (0.3%)
Myocardial infarction has been observed in patients with a history of myocardial infarction.
5. Congestive cardiac failure
Congestive cardiac failure has occurred.
6. Pulmonary edema
Pulmonary edema has occurred.
7. Bronchospasm
Bronchospasm has occurred.
8. Adult respiratory distress syndrome (ARDS)
ARDS has occurred.
9. Renal failure
Renal failure has occurred.
10.Hemolytic uremic syndrome (0.3%)
Because hemolytic uremic syndrome has occurred, administration should be discontinued if
signs of microangiopathic hemolytic anemia such as a rapid decrease in hemoglobin
accompanied by platelets decreased, bilirubin increased, creatinine increased, BUN increasedand LDH increased are observed. Renal failure may be reversed by discontinuing

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administration, and may require dialytic treatment.
11.Skin disorder (incidence unknown)
Severe skin disorders (erythema, blister, desquamation, etc.) have occurred.
12.Hepatic function disorder, jaundice (incidence unknown)
Severe hepatic function disorders such as AST (GOT), ALT (GPT) and Al-P increased, andjaundice have occurred.
Contraindications
1. Patients with severe bone marrow depression [bone marrow depression may worsen andbecome fatal.]
2. Patients with interstitial pneumonia or pulmonary fibrosis that is clear on a chest X-ray AND
is accompanied by clinical symptoms [symptoms may worsen and become fatal.]
3. Patients undergoing radiotherapy in the chest area [there are reported cases in overseas clinicalstudies of the concomitant use of gemcitabine and definitive radiotherapy of the chest
resulting in serious esophagitis and pneumonitis that have lead to death.]
4. Patients with a complicating severe infection [infection may worsen and become fatal.
5. Patient with a history of a severe hypersensitivity to components of gemcitabine.
6. Pregnant woman or woman of childbearing potential [teratogenic effects and embryofetal
lethality are reported in animal studies (mice and rabbit).]Main interactions
Contraindications for concomitant use
1. Irradiation of the chest1) Clinical symptoms and interventions
When gemcitabine (1000 mg/m2/day once per week administered prior to irradiation) anddefinitive radiotherapy of the chest (2 Gy/day 5 times/week) were used concomitantly for 6
weeks in an overseas clinical study, severe esophagitis and pneumonitis were developedthat lead to death. Since no optimal dose has been established for gemcitabine when usedconcomitantly with radiation exposure, concomitant use of gemcitabine with radiotherapyof the chest should be avoided as it is expected to have a radiosensitizing effect.
2) Mechanism
In a basic study, the effects of radiation exposure increased dose-dependently withgemcitabine treatment, where the drug was observed to cause increased radiosensitivity.
Precautions for concomitant use
1. Abdominal irradiation
1) Clinical symptoms and interventions
Localized complications that became severe have occurred upon concomitant use of
gemcitabine and abdominal radiotherapy (external irradiation). Note that the safety ofconcomitant gemcitabine use with intraoperative irradiation has not been confirmed.
2) Mechanism
In a basic study, the effects of radiation exposure increased dose-dependently withgemcitabine treatment, where the drug was observed to cause increased radiosensitivity.
2. Other antineoplastic drugs (alkylating agents, antimetabolic agents, antibiotics, alkaloids, etc.)
1) Clinical symptoms and interventions
Bone marrow depression has been exacerbated.
2) Mechanism
Both study drugs cause bone marrow depression.

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7.1.2. S-1
Product name: TS-1 capsule (Taiho Pharmaceutical Co., Ltd.), 20 mg/capsule, 25 mg/capsule
Mechanism of action
TS-1 is a preparation composed of tegafur (FT), gimeracil (CDHP) and oteracil potassium(Oxo), and its antitumor effect after oral administration is based on the gradual change of FT
to 5-FU within the body.
CDHP selectively and competitively inhibits DPD, which is a catabolic metabolizing enzymeof 5-FU that is mainly distributed in the liver, so increasing the concentration of FT-derived
5-FU. This increase in 5-FU concentration results in sustained high concentrations of
5-fluoronucleotides (phosphorylated metabolites of 5-FU) in the tumor, enhancing theirantitumor effect. Furthermore, oral administration of Oxo results in its distribution mainly indigestive tissues where it selectively and competitively inhibits orotate
phosphoribosyltransferase, which selectively suppresses the formation of 5-fluoronucleotides
from 5-FU. This is believed to mitigate the gastrointestinal toxicity of 5-FU without
decreasing the potent antitumor effect of 5-FU.
The main mechanism of action of 5-FU is the binding of its active metabolite FdUMP todUMP, forming a ternary complex with thymidylate synthase and folate analogs, thereby
inhibiting DNA biosynthesis. 5-FU is also said to be changed to FUTP, which impedes RNA
function.
Indications
Gastric cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer, inoperable
or recurrent breast cancer, and pancreatic cancer
Dosage and administration
The initial dose (first dose) in adults is normally one of the standard doses below according to
the patient’s body surface area. It is taken twice daily, once after breakfast and once after
evening meal, administered orally for 28 days continuously, followed by a 14-day rest period.
This is taken as 1 course of treatment and repeated.
Initial standard dose (equivalent
Body surface area
tegafur dose)>1.25m２
40 mg/administration≥1.25m２, <1.5 m２
50 mg/ administration
60 mg/ administration≥1.5 m２
Note that the dose will be increased or reduced as appropriate according to the condition of
the patient. Dose increases and reductions will take place at steps of 40 mg, 50 mg, 60 mg and
75 mg/administration. The dose will be increased by single steps starting from the initialstandard dose if there are no abnormal laboratory measurements (hematology, hepatic andrenal function measurements) and no gastrointestinal symptoms that are deemed to be causedby administration of S-1, if there are no problems with safety, and if a dose increase is judged
feasible. Dose increases will be limited to a maximum 75 mg/administration. In addition, dose
reductions will normally take place by single steps to a minimum dose of 40
mg/administration.
Main pharmacokinetics
In the 72 hours following a single, oral postprandial administration of 32-40 mg/m2 of TS-1 in
12 cancer patients, compared to the administered dose, 52.8% of gimeracil (CDHP), 7.8% oftegafur (FT), 2.2% of oteracil potassium (Oxo), 11.4% of the metabolite cyanuric acid (CA)and 7.4% of the metabolite fluorouracil (5-FU) were excreted in patients’ urine.
Main adverse drug reactions

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Hematological

Hepatic

Renal
Gastrointestinal

Dermatologic

Hypersensitivity
NeuropsychiatricCirculatory

OcularOther≥5%: White blood cells decreased, neutrophils decreased, platelets
decreased, red blood cells decreased, hemoglobin decreased,
hematocrit decreased
0.1 to <5%: Bleeding tendency (subcutaneous bleeding spot, epistaxis,
abnormal clotting factor), eosinophilia, white blood cells increased,
lymphocytes decreased≥5%: AST (GOT) increased, ALT (GPT) increased, bilirubinincreased, Al-P increased
0.1 to <5%: Jaundice, urobilinogen urine positive
0.1 to <5%: BUN increased, creatinine increased, proteinuria,
hematuria≥5%: Anorexia, nausea/vomiting, diarrhea, stomatitis
0.1 to <5%: Abdominal pain, enlarged feeling of abdomen, epigastricpain, gastritis, borborygmus, pale feces, constipation, angularstomatitis, cheilitis, glossitis, thirst, dysgeusia≥5%: Pigmentation
0.1 to <5%: Erythema, desquamation, flushing, blister, hand and footsyndrome, skin ulcer, dermatitis, alopecia, nail abnormality,
paronychia, herpes simplex, dry/rough skin
Incidence unknown: Photosensitivity, discoid lupus
erythematosus-like eruption≥5%: Rash
0.1 to <5%: Pruritis≥5%: General malaise
0.1 to <5%: Numbness, headache, headache dull, dizziness
Incidence unknown: Light-headedness
0.1 to <5%: Blood pressure decreased, blood pressure increased, ECG
abnormal, Raynaud symptoms
Incidence unknown: Palpitations
0.1 to <5%: Lacrimation, conjunctivitis, keratitis, eye pain, visualacuity reduced
Incidence unknown: Dry eye≥5%: LDH increased, total protein decreased, albumin decreased
0.1 to <5%: Pyrexia, generalized hot feeling, whinitis, pharyngitis,
sputum, glycosuria, sugar blood level increased, edema, myalgia, CK(CPK) increased, arthralgia, electrolyte abnormality (serum sodiumincreased, serum sodium decreased, serum potassium increased, serum
potassium decreased, serum calcium increased, serum calcium
decreased, serum chloride increased, serum chloride decreased),
weight decreased
Incidence unknown: Serum amylase increased

Serious adverse drug reactions (important adverse drug reactions)
1. Bone marrow depression, hemolytic anemia
Because hemolytic anemia (incidence unknown) and symptoms of severe bone marrowdepression such as panhemocytes decreased, agranulocytosis (Symptoms: pyrexia, pharyngeal
pain, malaise, etc.), white blood cells decreased, anemia and platelets decreased have occurred,patients should be observed carefully and appropriate action taken such as discontinuation ofadministration if an abnormality is observed.
2. Disseminated intravascular coagulation (DIC): Because DIC (0.3%) has occurred, patientsshould be observed carefully and if an abnormal hematology measurement, such as platelet
count, serum FDP level or plasma fibrinogen concentration is observed administration should
be discontinued and appropriate treatment given.

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3. Severe liver disorder, such as fulminant hepatitis (incidence unknown)
4. Dehydration: Because severe diarrhea has occurred and lead to dehydration (incidence
unknown), patients should be observed carefully and if such symptoms are observed
appropriate action taken such as discontinuation of administration and fluid replacement.
5. Severe enteritis: Because severe enteritis (0.6%) has occurred, patients should be observed
carefully and if symptoms such as severe abdominal pain or diarrhea occur administration
should be discontinued and appropriate treatment given.
6. Interstitial pneumonia: Because interstitial pneumonia (0.3%) (Initial symptoms: cough,shortness of breath, dyspnea, pyrexia, etc.) has occurred, patients should be observed carefully
and if an abnormality is observed appropriate action taken, such as discontinuation ofadministration, exams such as chest X-rays, and administration of corticosteroids.
7. Severe stomatitis, gastrointestinal ulcers, gastrointestinal hemorrhage and gastrointestinal
perforation: Because severe stomatitis (incidence unknown), gastrointestinal ulcers (0.6%),
gastrointestinal hemorrhage (incidence unknown) and gastrointestinal perforation (incidence
unknown) have occurred, patients should be observed carefully and if an abnormality isobserved administration should be discontinued, necessary exams such as abdominal X-rays
undertaken and appropriate treatment given.
8. Acute renal failure: Because severe renal disorders (incidence unknown) such as acute renal
failure have occurred, patients should be observed carefully and if an abnormality is observed
administration should be discontinued and appropriate treatment given.
9. Stevens-Johnson syndrome and Lyell syndrome: Because Stevens-Johnson syndrome andLyell syndrome (incidence unknown) have occurred, patients should be observed carefully
and if an abnormality is observed administration should be discontinued and appropriate
treatment given.
10.Neuropsychiatric disorders including leukoencephalopathy, etc.: Because
leukoencephalopathy (main symptoms being consciousness disturbed, cerebellar ataxia,
dementia-like symptom) and consciousness disturbed, disorientation, somnolence, memory
ability decreased, extrapyramidal symptoms, language disorder, quadriplegia, gait disturbance,
urinary incontinence, perceptual disturbance (all of which incidence unknown) and the likehave occurred, patients should be observed carefully and administration discontinued if any
such symptoms are observed.
11.Acute pancreatitis: Because patients acute pancreatitis (incidence unknown) has occurred,patients should be observed carefully and if abdominal pain, serum amylase increased, etc. isobserved administration should be discontinued and appropriate treatment given.
12.Rhabdomyolysis: Because rhabdomyolysis (incidence unknown) characterized by myalgia,
feelings of weakness, CK (CPK) increased and myoglobin blood/urine increased has occurred,
if such symptoms occur administration should be discontinued and appropriate treatment
given. In addition, care should be taken to watch for acute renal failure caused byrhabdomyolysis.
13.Anosmia: Because dysosmia has occurred and lead to anosmia (incidence unknown), patientsshould be observed carefully and appropriate action taken such as discontinuation ofadministration if an abnormality is observed.
Contraindications
1. Patients with a history of severe hypersensitivity to components of S-1
2. Patients with severe bone marrow depression [bone marrow depression may worsen andbecome fatal.]
3. Patients with a severe renal disorder [renal excretion of gimeracil, an inhibitor of a catabolic
metabolizing enzyme of fluorouracil, may be markedly reduced, increasing the bloodconcentration of fluorouracil, and causing adverse drug reactions such as bone marrowdepression to develop strongly.]
4. Patients with a severe liver disorder [liver disorder may worsen.]
5. Patients currently taking another fluorinated pyrimidine antineoplastic drug (including

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concomitant therapy with such drugs)
6. Patients currently taking flucytosine
7. Pregnant women or women of childbearing potential
Main interactions
Contraindications for concomitant use
1. Fluorinated pyrimidine antineoplastic drugs< Fluorouracil (5-FU, etc.), tegafur/uracil combination preparations (UFT, etc.), tegafur(futraful, etc.), doxifluridine (furtulon), capecitabine (xeloda), carmofur (mifurol) >Folinate/tegafur/uracil therapy (Uzel, UFT, etc.)
Levofolinate/fluorouracil therapy (Isovorin, 5-FU, etc.)
Fluorinated pyrimidine antifungal drugs < Flucytosine (Ancotil, Domerajin, Cocol) >1) Clinical symptoms and interventions
Concomitant use may quickly cause severe blood disorders and gastrointestinal disorders
such as diarrhea and stomatitis. Note that these drugs (therapies) should not be administered
within at least 7 days of discontinuing S-1 treatment. Furthermore, when administering S-1
after stopping treatment with of any of these drugs, administration of S-1 should be started
after an appropriate period of time considering the effects of these drugs.
2) Mechanism
Catabolism of administered fluorouracil or fluorouracil derived from administeredfluorinated pyrimidine is inhibited by gimeracil, resulting in a marked increase in blood
fluorouracil concentration.
Precautions for concomitant use
1. Phenytoin
1) Clinical symptoms and interventions
Because phenytoin toxicity (queasy/vomiting, nystagmus, movement disorder, etc.) has
occurred, patient condition should be observed carefully. Appropriate action should betaken such as discontinuation of administration if an abnormality is observed.
2) Mechanism
Phenytoin metabolism is suppressed by tegafur, resulting in an increase in the bloodconcentration of phenytoin.
2. Warfarin potassium
1) Clinical symptoms and interventions
Because S-1 enhances the action of warfarin potassium, attention should be paid withrespect to fluctuations in blood coagulability.
2) Mechanism
Mechanism unknown.
3. Other antineoplastics and radiation exposure, etc.
1) Clinical symptoms and interventions
Because S-1 exacerbates adverse drug reactions such as blood disorders and gastrointestinal
disorders, patient condition should be observed carefully. Appropriate action such as dose
reduction or dose interruption should be taken if an abnormality is observed. Because S-1
enhances the action of warfarin potassium, attention should be paid with respect tofluctuations in blood coagulability.
2) Mechanism
Adverse drug reactions are exacerbated by drug-drug interactions.

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7.2.

Anticipated adverse events

Anticipated adverse drug reactions are as shown below.
7.2.1. Anticipated adverse drug reactions caused by chemotherapy
See protocol section 7.1. “Drug information” for information regarding anticipated adverse drug
reactions.
7.2.2. Anticipated adverse events caused by recurrence of the primary disease
Anticipated adverse events caused by recurrence of the primary disease will be described using
short names from CTCAE ver3.0. These adverse events are only deemed anticipated adverse events
after having occurred with the primary disease deemed the potential cause.
General condition: Fatigue, weight loss
Lymphatics: Edema: head and neck, Edema: limb, Edema: trunk/genital, Edema: viscera
Metabolic/laboratory: Hypoalbuminemia, AST, ALT, bilirubin, alkaline phosphatase
Pain: Pain-{site}
7.2.3. Anticipated adverse events caused by concomitant drug use
This section states the main adverse drug reactions for frequently used concomitant drugs. See
the package insert of each concomitant drug for more details. These adverse events are only
anticipated in the event of concomitant use of the concomitant drugs.
Serotonin (5-HT3) antagonists
Drugs: Azasetron hydrochloride (Serotone®), gradisetron hydrochloride (Kytril®),
tropisetron hydrochloride (Navoban®), ramosetron hydrochloride (Nasea®),
ondansetron (Zofran®, Zydis®)Adverse drug reactions: Headache, feeling of headache, fever, chills, hepatic function abnormal(AST, ALT, LDH, total bilirubin increased), palpitations, rash, diarrhea,
constipation
Granulocyte colony-stimulating factor (G-CSF)
Drugs: Nartograstim (Neu-up®), filgrastim (Gran®), lenograstim (Neutrogin®)
Adverse drug reactions: (Severe adverse drug reactions): Interstitial pneumonia, ARDS, splenic
rupture(Other adverse drug reactions): Pyrexia, rash/redness, ALP increased, LDH
increased, AST/ALT/bilirubin increased, urate/creatinine increased, CRP increased,bone pain, low back pain, chest pain, arthralgia, nausea/vomiting, headache,malaise, palpitations, skin disorder with neutrophil infiltration/painful
erythema/pyrexia
Adrenocortical hormones
Drugs: Dexamethasone (Decadron®), betamethasone (Rinderon®)
Adverse drug reactions: (Severe adverse drug reactions): Inducement/exacerbation of infection,
adrenal cortical insufficiency, sugar blood level increased, peptic ulcer, hemorrhageof digestive tract, gastrointestinal perforation, pancreatitis, esophagitis, convulsion,increased intracranial pressure, epidural lipoma, mental aberration, depressive state,osteoporosis, aseptic necrosis (femur, humerus, etc.), myopathy, tendon rupture,glaucoma, ocular hypertension, posterior capsule opacification, thrombosis, cardiac
failure congestive, asthma attack exacerbated(Others): Moon face, buffalo hump, blood pressure increased, Na and water
retention (edema), weight increased, hypokalemic alkalosis, Cushing-like symptoms,
menstrual disorder, sperm motility/count increased/decreased, acne, hypertrichosis,
alopecia, pigmentation, thinning of/fragility of skin, ecchymosis, striae, purpura,facial erythema, panniculitis, hypersensitivity symptom (rash), pruritus, euphoria,

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sleep loss, headache, dizziness, paridrosis, polyuria, white blood cells increased,
hepatic steatosis, AST/ALT/ALP increased, hyperlipidemia, hypercholesterolemia,
steroid nephropathy, nausea/vomiting, gastralgia, heartburn, enlarged feeling of
abdomen, thirst, diarrhea, increased appetite, anorexia, retinal disorder caused bycentral serous chorioretinopathy, proptosis, myalgia, arthralgia, pyrexia, fatigue
Pain relief drugs
Drugs: Morphine (MS Contin®, Kadian®, Anpec®, Prepenon®, Opso®), oxycodone HCl(Oxycontin®)
Adverse drug reactions: Vomiting, constipation, sleepiness, anxiety, depressive state,confusion/hallucination, urination impaired, respiratory depression
Drugs: Fentanyl citrate (Durotep®)
Adverse drug reactions: (Severe adverse drug reactions): Dependency, respiratory depression(Other adverse drug reactions): Blood pressure increased, tachycardia, bradycardia,
blood pressure decreased, sleepiness, unrest, sleep loss, somnolence, amnesia,dizziness, irritability, hallucination, euphoria, headache, confusion, application sitepruritus, rash, pruritus, application site erythema, erythema, constipation, queasy,
vomiting, diarrhea, thirst, hepatic function abnormal, urinary retention, pyrexia,
malaise, sweaty
7.2.4. Anticipated postoperative adverse events and complications
This section describes the anticipated postoperative adverse events and complications. These
adverse events are only deemed anticipated adverse events after having occurred with surgery
deemed the potential cause.
Gastrointestinal: Gastrointestinal fistula (biliary fistula), gastrointestinal leak (pancreatic fistula),
gastrointestinal obstruction (adherent, etc. mechanical ileus), gastrointestinal ileus(paralytic ileus)
Hemorrhage: Gastrointestinal hemorrhage, surgery related hemorrhage (intra-abdominal
hemorrhage, wound bleeding, etc.)
Infection: Infection with Grade 0-2 neutrophils decreased (intra-abdominal abscess, cholangitis,
peritonitis, wound infection, etc.)
Vascular: Thrombosis (deep vein thrombosis, pulmonary embolus, etc.)
Pain
7.3.

Evaluation of adverse events/adverse drug reactions

CTCAE v3.0 Japanese translation JCOG/JSCO will be used to evaluate adverse events/adverse
drug reactions.
Adverse events will be graded according to the grade 0-4 definition they most closely resemble.
While the original CTCAE regards a treatment-related death as a grade 5 adverse event, in thisstudy, treatment-related deaths will be entered into records forms as a grade 4 adverse event.
Observations regarding the causal relationship between an adverse event and death after atreatment-related death will be entered into the “Circumstances at death” field of the clinical trial
end report form and follow-up form, and will require expedited reporting. (An investigation
conducted later, which will include expedited reporting, will determine whether the adverse eventis grade 5.)
The grading of the toxicity-related adverse events noted in protocol section 8.3. “Investigations
and assessments during the study period” will be entered into relevant records forms. Other
toxicity-related adverse events will be entered by name along with the worst relevant grade into the“Other” field of the progress report, but only for toxicity-related adverse events that are grade 3 orabove.
The grade entered into records forms will always also be entered into the medical record.

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8. Items for evaluation, laboratory tests and evaluation schedule*Items for evaluation and laboratory tests will be implemented as described in this section.
However, it is recommended that abdominal CT scans be performed from the abdomen to thepelvis, with MRI also available as a substitute to be used in case of a contrast media allergy.
8.1.

Items evaluated prior to registration

The below items will be evaluated prior to registration.
8.1.1 Lesion evaluation: Evaluation within 2 weeks prior to registration
1) Abdominal CT
2) Chest X-ray (2 directions); lung window
3) Resting 12-lead ECG
8.1.2 Laboratory tests: Evaluation within 1 week prior to registration
4) Hemogram: WBC, RBC, Hb, Ht, Plt, differential white blood count5) Biochemistry: TP, Alb, T-Bil, ALP, AST, ALT, LDH, Na, K, BUN, Cr, Ca, blood sugar
6) Blood serum: CRP
7) Tumor markers: CEA, CA19-9
8) Urinalysis (spot urine): Qualitative urine glucose, qualitative urinary protein
8.1.3 Subjective symptoms: Evaluation on registration day or prior day9) PS (ECOG), body weight, HRQOL
8.2.

Categorization of treatment period, observation period and follow-up period

In this study, the protocol treatment period and all periods after protocol treatment has stopped
will be divided into the three categories below, with items for evaluation and methods of evaluationprescribed for each period.
Treatment period:
From the start of treatment to 30 days after the final day oftreatment in order to evaluate adverse events related to protocol treatment. If
posttreatment is started before 30 days after the final day of treatment, thetreatment period shall be until the day before the start of posttreatment.
Observation period:
The period after the completion or discontinuation of protocoltreatment during which the patient will be evaluated for recurrence.
Consequently, the observation period will be from 31 days after the final day ofadministration to the day recurrence is confirmed, or the final follow-up
observation of this study. There will be no observation period if recurrence isconfirmed during the treatment period.
Follow-up period:
From the end of the treatment period and observation period until
the final follow-up observation of this study or until death.

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8.3.

Investigations and evaluations during the treatment period

1) Subjective symptoms
The items below will be evaluated at each outpatient visit (at least once fortnightly, or at least
once weekly during inpatient care), and the worst measurements/results based on CTCAE v3.0
entered into records forms (case report forms).
Constitutional symptoms:
Fatigue, fever
Dermatology/skinHyperpigmentation, hand-foot skin reaction
Gastrointestinal:
Anorexia, diarrhea, nausea, vomiting, mucositis(functional/symptomatic)-oral cavity
Infection:
Infection with Grade 3 or 4 neutrophils (fever of unknown origin)
Infection with Grade 3 or 4 neutrophils (documented clinically)-{Catheter-related infection, biliary tree, gallbladder, bronchus, lung(pneumonia), pharynx, upper respiratory NOS, bladder, kidney,urinary tract NOS}
Infection with Grade 0 to 2 neutrophils-{Catheter-related infection, biliary tree, gallbladder, bronchus, lung(pneumonia), pharynx, upper respiratory NOS, bladder, kidney,urinary tract NOS}
Ocular/visual
Watery eye2) Laboratory tests
The items below will be evaluated at each outpatient visit (at least once fortnightly, or at least
once weekly during inpatient care), and the worst laboratory measurements entered into records
forms (case report forms).
Hemogram: WBC, Hb, Plt, neutrophil count
Biochemistry: Alb, T-Bil, AST, ALT, ALP, Cr, Na, K, Ca
3) Checking for recurrence
Abdominal CT and chest X-ray exams will be conducted at least once every 3 months (3 and 6
months after starting treatment) to check for recurrence.
Tumor markers (CEA, CA19-9) will be examined once monthly.
4) Checking patients’ general condition
HRQOL and PS will be checked once every 3 months (3 and 6 months after starting treatment).
8.4.

Investigations and evaluations during the observation period

1)

Checking for recurrence
Abdominal CT and chest X-ray exams will be conducted at least at the frequencies shown below
to check for recurrence.
Within 2 years after registration: Every 3 months
From 2 years after registration: Every 6 months
Tumor markers (CEA, CA19-9) will be examined at least at the frequencies shown below.
Within 2 years after registration: Every 3 months
From 2 years after registration: Every 3 months
2) Checking patients’ general condition
HRQOL and PS will be checked once every 6 months.

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8.5.

Investigations and evaluations during the follow-up period

・Presence of posttreatment
・Site of recurrence・If posttreatment is being used, the treatment method, start date and general condition at start ofposttreatment
・If posttreatment is not being taken, the reasons for its absence
・Date of death, or date of the final confirmation of survival
・In case of death, the cause of death・HRQOL and PS will be checked once every 6 months. If HRQOL or PS cannot be checked forany reason, the reason will be recorded in the questionnaire form.
CautionEven when direct patient follow-up is not feasible due to hospital transfer or other reasons,inquiries will be made with the destination of hospital transfer, etc. as possible to confirm
whether the patient is alive or dead, and the results of the inquiry will be entered into the medical
record.

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8.6.

Study calendar

General condition
Subjective symptoms
Body weight
HRQOL, PS
Laboratory tests
WBC, RBC, Hb, Ht, Plt,
differential white blood countWBC, Hb, Plt, neutrophil
count
TP, Alb, T-Bil, ALP, AST,
ALT, LDH, Na, K, BUN, Cr,
Ca, blood sugar, CRP
Alb, T-Bil, AST, ALT, ALP,
Cr, Na, K, Ca
Urinalysis (qualitative urinary
protein/urine glucose)
12-lead ECG
Lesion evaluation
CEA, CA19-9
Chest X-ray (2 directions)Abdominal CT (up to pelvis)
Submission of records forms
Patient registration card
Pre-treatment report
Progress report

Treatment end report

Beforeregistration

Treatment
period*

† a)
† a)
† a)

‡
§
(3)

Observation
periodWithin 2 years
after
registration

Observation
period From 2
years after
registration

(6)

(6)

(3)
(3)
(3)

(3)
(6)
(6)

Follow-up
period

(6)

† b)
‡
† b)
‡
† b)
† c)
† b)
† c)
† c)

(1)
(3)
(3)

†
†
†
End of eachcourse†After end oftreatment
periodQuestionnaire about daily
† a)
(3)
(6)
(6)
(6)
living
Follow-up card
(6)
(6)
(12)
(12)
†: Required‡: Every outpatient visit (at least once fortnightly, or at least once weekly during inpatient care)§: As necessary(1): Evaluated every month, (3): Evaluated every 3 months, (6): Evaluated every 6 months, (12): Evaluated every 12
monthsa) Evaluation on registration day or day before registration, b) Evaluation within 1 week prior to registration, c)
Evaluation within 2 weeks prior to registration*Note that the treatment period is until 30 days after the final day of administration, or until the day before the start ofposttreatment.

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9. Data collection
9.1.

Records forms (case report forms: CRFs)

9.1.1. Data submission
Excluding the patient registration card, in this study data submission will take place via an EDC
system using CRFs in a PDF file format. Investigators or CRCs will submit data via the EDC
system to the CSPOR data center during the progress of the study for all registered patients up tocompletion of the study. If entry or input is performed by a CRC, he/she will obtain confirmationfor entry or input from an investigator. Details of the data to be submitted, procedures for
submission and the timing of submissions are shown below.
9.1.2. Types of records forms and deadlines for submission
The CRFs to be used in this study and deadlines for submission are shown below.
1) Case registration card
-Faxed to CSPOR data center
2) Pre-treatment report-Promptly after the case registration card
3) Progress report-Promptly at the end of every course
4) Treatment end report-Promptly after the end of the treatment period5) Follow-up card-Every 6 months within 2 years after registration,then every 12 months from 2 years after registration
6) HRQOL survey (questionnaire about daily living)-By post within 1 month after survey
completion
7) Adverse event expedited primary report -As necessary8) Adverse event report-As necessary
9.1.3. Submission of records forms
・ Once the CSPOR data center has been informed of IRB review and approval and conclusion of aclinical trial agreement/contract, three removable USB drives (one USB drive containing the
EDC system, one USB drive to be used for backing up, and one USB drive for submission ofdata) and a study start pack will be sent by post from the CSPOR data center to the principal
investigator at the study site.
・ Of the CRFs mentioned in protocol section 9.1.2 “Types of records forms and timings for
submission”, CRFs 2) to 5) will be included in the EDC system in PDF file format. To submit
data to the data center, the USB drive containing the EDC system and the USB drive for backing
up will be simultaneously inserted into a PC, the system will be started up, a PDF-format CDF
will be navigated to within the opened browser, and the required data entered into the CRF. Afterentry is complete, data will be copied from the backup USB drive to the USB drive for datasubmission, and the USB for data submission will be sent by post to the CSPOR data center by aprescribed method (after the data is imported by the data center, the USB for data submission will
be returned to the study site by post). After that, if inquiries arise as a result of the centralized
monitoring performed at the CSPOR data center, the inquiries will be sent to study sites using
print outs of CRFs that contain the submitted data.
・ Because patient registration cards and RCFs are needed promptly during registration, they will besent by fax.
・ Regarding follow-up cards, the study site will be contacted every six months within 2 years after
registration and every 12 months from 2 years after registration by the CSPOR data center torequest the conduct of investigations and to request the submission of data via the EDC system.
・ Regarding the HRQOL survey (questionnaire about daily living), the survey form will becollected by a CRC or investigator, whereupon the CRC or investigator will determine the PS andenter it into the survey form. The CRC or investigator will send the survey form to the CSPOR
data center by post within 1 month of survey completion.
・ In order to avoid the disclosure of personal patient information, patient registration numbers will

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be used during communication with the CSPOR data center and study site medical record
numbers will not be used.

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9.1.4. Correction of records forms
Although the CSPOR data center and study administrators take extreme care during the
preparation of records forms, it is possible that missing or inappropriately classified required items
and the like are discovered in records forms after commencement of the study. In such cases,
records forms will be corrected upon the consent of the head of the data center and a study
administrator, provided the change does not mean the scope of the data prescribed for collection in
protocol section 8. “Items for evaluation, laboratory tests and evaluation schedule” will be
exceeded, and provided the correction is judged not to increase the clinical or financial burden on
registered patients. Corrections to records forms that do not require amendment of the protocol
itself will not be regarded as protocol amendments. Study site rules will be followed as to whether
a records form correction will be reported to the study site IRB.

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10. Reporting of adverse events
According to the provisions of this chapter, in the event of a “severe adverse event” or“unanticipated adverse event”, the study site study manager will report the event to the study
administrator/study representative.
Note that reports of adverse drug reactions, etc. made to the Minister of Health, Labour andWelfare based on the Pharmaceutical Affairs Act (Contact: Pharmaceutical and Food Safety
Bureau, Ministry of Health, Labour and Welfare, Fax: 03-3508-4364,
http://www.pharmasys.gr.jp/info/houkoku.html), reports of severe adverse events, etc. made byeach study site to the head of the study site based on ethical guidelines for clinical research (Public
Notice of the Ministry of Health, Labour and Welfare, No. 255,
http://www.mhlw.go.jp/topics/2003/07/tp0730-2.html), and contact made by study sites withcorporate enterprises regarding adverse drug reactions should be done appropriately according to
the rules of each study site and shall be the responsibility of the study manager of each study site.
10.1. Adverse events of which there is an obligation to report
10.1.1. Adverse events of which there is an obligation for expedited reporting
Adverse events to which any of the below is applicable will be subject to expedited reporting.
(1) All deaths during protocol treatment or within 30 days after the final day of protocol treatment
Expedited reporting irrespective of causal relationship to protocol treatment. Adverse events
within 30 days after the final day of protocol treatment will be subject to expedited reportingeven if posttreatment has already started after discontinuation of protocol treatment.
(30 days counting day 0 as the final day of protocol treatment)(2) Unanticipated Grade 4 non-hematological toxicities (adverse events outside the blood/bonemarrow category in CTCAE ver3.0)
Grade 4 non-hematological toxicities not included among serious adverse drug reactions in
protocol section 7.2 “Anticipated adverse events”. Events that occur during protocol treatment
or within 30 days from the final day of protocol treatment will be subject to expedited
reporting irrespective of causal relationship, and events that occur from 31 days after the final
day of protocol treatment and onwards will be subject to expedited reporting only if a causal
relationship to protocol treatment is identified (related or probably related).
10.1.2. Adverse events of which there is an obligation for normal reporting
Adverse events to which any of the below is applicable will be subject to normal reporting.
Of adverse events that fall under (2) and (3) below, events that occur within 30 days from thefinal day of protocol treatment will be subject to normal reporting irrespective of causal
relationship, and events that occur from 31 days after the final day of protocol treatment andonwards will be subject to normal reporting only if a causal relationship to protocol treatment is
identified (related or probably related).
(1) Deaths that occur from 31 days after the final day of protocol treatment and onwards for whicha causal relationship cannot be ruled out
Applicable to deaths that are suspected to be treatment-related. Not applicable to deaths
clearly caused by the primary disease.
(2) Anticipated Grade 4 non-hematological toxicities (adverse events outside the blood/bonemarrow category in CTCAE ver3.0)
Grade 4 non-hematological toxicities not included among serious adverse drug reactions in
protocol section 7.2 “Anticipated adverse events”. Be aware that severe adverse events will be
subject to normal reporting even if they are anticipated.

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Grade 2 or 3 adverse events not included in protocol section 7.2. “Anticipated adverse events”
or in the drug package insert.
(4) Permanent or significant disability/incapacity
Aplastic anemia, myelodysplastic syndrome, secondary cancer, etc.
(5) Other important medical events
Events that do not fall under (1) or (2) in section 10.1.1., or (1) to (4) in section 10.1.2., but
comprise important information that should be shared between participating study sites.
10.2. Reporting obligations of the study site study manager and reporting procedures
10.2.1. Expedited reporting
When an adverse event occurs that is subject to expedited reporting, an investigator willpromptly inform the study site study manager. If the study site study manager is not available, a
study site coordinator or investigator must take on the responsibilities of the study site study
manager.
Primary reporting:Within 72 hours of learning of an adverse event, the study site study manager will fill in thematters specified in an adverse event expedited primary report, fax it to the study
representative and also contact the study representative by phone.
Secondary reporting:Within 7 days of learning of an adverse event, the study site study manager will fill in thematters specified in an adverse event report, prepare a case report (A4, no restriction on
format) that contains more detailed information on the adverse event to accompany theadverse event report, and send both to the study representative by post or by fax. In order toprioritize the prompt communication of information, the report may be sent even if some
sections could not be completed.
Tertiary reporting:Within 15 days of learning of an adverse event, the study site study manager will fill in all
sections of an adverse event report that could not previously be completed, and send it to thestudy representative by post or by fax. In cases of autopsy the postmortem examination will
also be appended.
10.2.2. Normal reporting
Within 15 days of learning of an adverse event, the study site study manager will fill in thematters specified in an adverse event report and send it to the study representative by post or byfax.
10.3. Responsibilities of the study representative/study administrators
10.3.1. Determining the need for suspension of registration and urgent notification of studysites
The study representative will determine the degree of urgency, importance and impact of thecontent of reports received from study site study managers and take measures as necessary such as
temporary suspension of registration (by contacting the data center and all participating study sites)and seeking urgent contact with study sites to inform them of matters. Depending on the degree ofurgency, the study representative may first contact the data center and study sites by phone thenagain later in document form within a prompt time frame (by fax, post or email).
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normal report falls under protocol section 10.1 “Adverse events of which there is an obligation toreport”, within 15 days of learning of the adverse event he/she will make a report of same adverse
event to the Efficacy and Safety Evaluation Committee in document form and request the Efficacy
and Safety Evaluation Committee also reviews the study representative’s own views of the given
adverse event and regarding suitable ways of addressing the adverse event.
The study representative should include in the report to the Efficacy and Safety Evaluation
Committee the adverse report expedited primary report and adverse event report received from thestudy site, as well as the conclusions of the study representative’s own examination into how to
respond to the adverse event (including a judgment on continuation/discontinuation the study). In
addition, for deaths within 30 days as described in section 10.1.1.(1) and deaths from 31 days
onwards as described in section 10.1.2.(1) that are judged treatment-related, and for anticipatedsevere adverse events as described in section 10.2.2.(2), the study representative should also
include his/her observations on the progress of individual patients and whether incidence of thegiven adverse event is within the anticipated range.
10.3.3. Notification of researchers at study sites
If the study representative has made a report to the Efficacy and Safety Evaluation Committee,
the study representative will notify the study site study manager of all participating study sites indocument form of the review and content of the recommendations of the Efficacy and Safety
Evaluation Committee.
If the study representative has not made a report to the Efficacy and Safety Evaluation
Committee, he/she will notify the study site study manager of the study site that made the report of
the findings of the study representative’s own observations on the matter.
10.3.4. Investigation of adverse events during periodic monitoring
During monitoring, the study representative/study administrators will carefully examine theadverse event reports included within the monitoring reports created by the CSPOR data center inorder to verify there are no errors in reports received from study sites. They will also verify that allreported adverse events have been listed in periodic monitoring reports.
10.4. Examination by the Efficacy and Safety Evaluation Committee
The Efficacy and Safety Evaluation Committee will review and examine the content of reports
according to procedures for clinical safety data management, and make recommendations to thestudy representative in document form with respect to how to address matters going forward,
including whether to continue registration and whether the protocol needs amendment.

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11. Assessment of efficacy and definition of endpoints
11.1. Definition of the analysis population
Periodic monitoring, interim analysis and final analysis will be performed on the analysis
populations as defined below.
11.1.1. All registered patients
All patients registered according to protocol section 5.1.1 “Registration procedure”, excluding
duplicate registrations and registrations made in error, will be included among All Registered
Patients.
11.1.2. All eligible patients
All patients included among All Registered Patients, excluding those identified as ineligible
patients upon examination of the treatment arms, will be included among All Eligible Patients.
Ineligible patients can only be included among All Eligible Patients by the judgment of aninvestigator, study site coordinator or the study site study manager. Approval of the study
representative is required to identify ineligible patients from treatment arms at final analysis,though at interim analyses and at analyses for academic presentations performed prior to
submission of periodic monitoring and the final analysis reports, with the understanding of thestudy administrator the data center is allowed to exclude patients from among All Eligible Patients
when identified as ineligible by a study administrator.
11.1.3. All Treated Patients
All patients among All Registered Patients administered the protocol treatment in whole or inpart will be included among All Treated Patients. With the understanding of a study administrator,
the data center may identify patients who took none of the protocol treatments as Untreated
Patients and decide whether to exclude them from the data aggregation performed for safety.
11.2. Endpoint definitions
11.2.1. Overall survival
The period starting from the registration date until the day of death by any cause.
・The cutoff point for surviving patients will be the date of the final confirmation of survival.
・The cutoff point of patients lost to follow-up will be the date of the final confirmation of survival
prior to the patient becoming lost to follow-up.
11.2.2. Relapse-free survival
The period starting from the registration date until the day that recurrence is confirmed.
・The cutoff for relapse-free patients will be the date of the final confirmation of survival.
・If a patient dies for a reason other than the primary disease while relapse-free, it will be deemedan event using the date of death.
・The cutoff for patients lost to follow-up will be the date of the final confirmation of the patient
being relapse-free prior to the patient becoming lost to follow-up.

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11.2.3. Adverse events
1. Incidence of adverse events
Taking All Treated Patients as the denominator, the frequency of the worst grade of each of the
below adverse events (toxicities) based to the CTCAE ver3.0 Japanese translation JCOG/JSCO
edition will be calculated during all courses.
Constitutional symptoms
Fatigue, fever
Dermatology/skin:Hyperpigmentation, hand-foot skin reaction
Gastrointestinal:
Anorexia, diarrhea, nausea, vomiting, mucositis(functional/symptomatic)-oral cavity
Infection:
Infection with Grade 3 or 4 neutrophils (fever of unknown origin)
Infection with Grade 3 or 4 neutrophils (documented clinically)-{Catheter-related infection, biliary tree, gallbladder, bronchus, lung(pneumonia), pharynx, upper respiratory NOS, bladder, kidney,urinary tract NOS}
Infection with Grade 0 to 2 neutrophils-{Catheter-related infection, biliary tree, gallbladder, bronchus, lung(pneumonia), pharynx, upper respiratory NOS, bladder, kidney,urinary tract NOS
Ocular/visual:
Watery eye
Blood/bone marrow: Hemoglobin, leukocytes, neutrophils, platelets
Metabolic/laboratory: Hypoalbuminea, ALT, AST, bilirubin, hypocalcemia, hypercalcemia,
creatinine, hyperkalemia, hypokalemia, hypernatremia, hyponatremia
Other than the above-described adverse events (toxicities), because only adverse events that are
non-hematological toxicities (blood/bone marrow category) of Grade 3 or above will be entered inrecords forms, as a general rule their incidence will not be calculated except for when specificadverse events are observed in high numbers.
2. Incidence of severe adverse events
Taking All Treated Patients as the denominator, the incidence of severe adverse events will becalculated as the proportion of subjects in whom any of the severe adverse events shown below
occurs, using the number of patients who experience at least one of these severe adverse events as
the numerator.
1) All deaths during the protocol treatment period, or within 30 days from the final day ofchemotherapy. (Deaths will be counted irrespective of causal relationship to protocol treatment.)2) Deaths from 31 days after the final day of chemotherapy onwards with a causal relationship toprotocol treatment that cannot be ruled out.
3) Grade 4 non-hematological toxicities (does not include adverse events in the blood/bone marrow
category).

11.2.4. Health-related QOL
Details shown in protocol section 12

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12. Health-related QOL
12.1. Objectives
Patients’ subjective assessment of their HRQOL will be compared as a secondary indicator forevaluation.
(1) The difference in the impact gemcitabine therapy and S-1 therapy have as adjuvant
chemotherapy in patients with resected pancreatic cancer will be compared.
(2) HRQOL during the entire survival period will be compared between the treatment arms as the
QALY.
12.2. HRQOL scale
EQ-5D23-25 will be used as the standardized measure of HRQOL ( Appendix). EQ-5D is a
simple measure of QOL and will be used to calculate QALY (5 levels of severity).
12.3. HRQOL survey schedule
The first survey will be completed before treatment, then upon entering the third and sixth monthof the 6-month protocol treatment period, and every 6 months thereafter.
In this study the administration schedule for the protocol treatment will vary, and some leeway
will be allowed with respect to the acceptable time (window) within which surveys are to becompleted. While surveys in the protocol treatment period should be completed upon entering thethird and sixth months of the protocol treatment period, as a general rule, the surveys may becompleted within a window of ±2 weeks of those times. During the observation period andfollow-up period, as a general rule, surveys may be completed within a ±1-month window.
12.4. Survey method
As a general rule, surveys will be implemented by a CRC at each survey time point before thestart of the next treatment course. Survey forms will be collected by a CRC or investigator. PS will
be determined by a CRC or investigator and entered on the survey form. A CRC or investigator willcollect survey forms and send them by post to the data center.
Note that in the event a patient is unable to fill in the survey form personally due to worsening of
his/her condition, as a general rule the CRC may implement the survey by reading out the survey
form to the patient. However, in such cases, this fact will be entered on the survey form.
12.5. Sample size
From experience of conduct of the N-SAS-BC02 trial, the minimum necessary sample size for
an HRQOL analysis is deemed to be around 300 patients.
12.6. Method of data analysis
The EQ-5D scores will be aggregated to produce the temporal change in each treatment arm,summarized to produce statistics for smaller numbers as necessary, and compared for an analysis ofvariance between treatment arms. Propensity scores and weighting, etc. will be used to impute
missing data. Details of the analytical plan, including QALY calculation (standard error calculationin particular), will be specified in a separate analytical plan.

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13. Statistical considerations
13.1. Main analyses and evaluation criteria
Through applying a proportional hazard model, a hazard ratio threshold of 1.25 will be used toverify the non-inferiority of the S-1 arm against the GEM arm in terms of overall survival.
Specifically, applying the proportional hazard model, non-inferiority will be verified if the 95%
confidence interval of the S-1 arm to GEM arm death hazard ratio does not exceed 1.25. A standard
log-rank test will also be performed between the treatment arms for reference. If non-inferiority isverified, the superiority of the S-1 arm over the GEM arm will also be tested using a log-rank test.
For purposes of interpretation, a normal approximation will be used to calculate the posterior
distribution of the log hazard ratio from a noninformative prior distribution, and a posterior
probability calculated that includes the log hazard ratio for both inside and outside theabove-described threshold (±log 1.25) and a stricter threshold of ±log 1.15. The assumption of thisinvestigation of proportional hazards between the treatment arms will be confirmed using a log-log
plot of a Kaplan-Meier curve. If a marked deviation from the proportional hazards assumption isobserved, the same investigation as described above will be performed for the 3-year cumulative
survival rate.
Note that QALY and Quality Adjusted Disease Free Survival (QADFY), which aremeasurements of QOL, will be compared between treatment arms in order to provide important
judgment criteria on which to base the selection of a primary treatment.
Adverse events and QOL will be examined along with the results of the primary endpoint, andone of the below conclusions will be reached for this study. Moreover, all data relating to endpoints
in this study must be presented to, and the final conclusion approved by, the Efficacy and Safety
Evaluation Committee.
1) If the hazard associated with S-1 therapy is <1/1.15, S-1 therapy will be recommended as
adjuvant chemotherapy for resected pancreatic cancer in Japan.
2) If the hazard associated with S-1 therapy is <1 or ≥1/1.15, non-inferiority will almost be verified
and S-1 therapy will be deemed a possible option as adjuvant chemotherapy for resected pancreaticcancer in Japan, while citing the probability of inferiority of S-1 therapy compared with GEM
therapy.
3) If the hazard associated with S-1 therapy is ≥1, the non-inferiority hypothesis will not have beenverified. GEM therapy will be the standard treatment as adjuvant chemotherapy for resectedpancreatic cancer, and S-1 therapy will not be used as adjuvant chemotherapy for resectedpancreatic cancer.
13.2. Planned sample size and follow-up period
With 1/1.15 chosen as the true hazard ratio between the S-1 arm and GEM arm and with astatistical power of 80%, a total 240 events (deaths) is needed across the treatment arms to verify
non-inferiority. The 3-year survival rate of the GEM arm will be set at 36% (and, based on theabove assumption, the anticipated 3-year survival rate in the S-1 arm is 41%), and assuming an
exponential distribution for the survival function (MST of 27.2 and 28.0 months, respectively) andthat 360 patients are registered evenly across both treatment arms during the 3 years, the expected
incidence of events at 1, 2 and 3 years after registration is 191, 237 and 270, respectively. From theabove, with 360 registered patients, interim analysis will take place at 1 year after the end ofregistration when there is anticipated to be 180 events, and final analysis will take place at 2 years
after the end of registration.
Note that the results of the above calculations are strongly dependent on the value of the base3-year survival rate (36%) and the exponentiality of the survival distribution. Because ofdifferences in patient selection resulting from the inclusion/exclusion criteria, differences in thepatient population itself, and survival benefits that are expected to result from posttreatment with

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S-1 and gemcitabine, the actual number of events may be expected to be fewer than the number
anticipated. It should be considered that extension of the follow-up period would be highly likely inthe case of a GEM arm 3-year survival rate of 40% and a hazard ratio that is lower by about 10%. It
is not definite that registration will proceed as planned. Consequently, incidence of events will bemonitored during and after registration and examined again at both interim and final analyses.
Although 1.25 is slightly high as a threshold for a non-inferiority study (1.15 to 1.2 is commonlyused), when conducted from the perspective of drug approval, a non-inferiority study is essentiallya way of obtaining a definite and quick evaluation of a treatment method that is believed to besuperior, and is not a methodology used to carry out a relative evaluation to choose between
treatments that are considered almost equivalent. Nevertheless, with the amount of information
obtained in a non-inferiority study, it is quite possible to carry out a relative comparison between
treatment arms using the confidence intervals of the hazard ratio or difference between survival
rates. For example, when a Bayesian process is used to calculate the posterior distribution of thelog hazard ratio from a noninformative prior distribution, non-inferiority of the S-1 arm against the
GEM arm is verified at a hazard ratio of exactly 0.97, where the posterior possibilities for
inferiority and non-inferiority of the S-1 arm against the GEM arm are 41% and 59%, respectively.
If a stricter threshold of 1.15 and hazard ratio of 1/1.15 (0.87) is used, the posterior probability thatthe hazard ratio lies outside it is 9.4% for inferiority and 19.7% for non-inferiority, and theposterior probability that the hazard ratio lies inside and can be considered clinically equivalent is
70.9%.
13.3. Patient handling, analysis population and data analysis
Proposals for patient handling, including treatment compliance, will be prepared by the Protocol
Drafting Committee prior to the end of registration, and implemented according to criteria
determined prior to interim analysis. Patients subject to the main analyses of overall survival andrelapse-free survival will be All Eligible Patients in whom study treatment has been started (theso-called full analysis set). Patients subject to analysis of adverse events will be patients in whomstudy treatment has been started (All Treated Patients). Patients that will be subject to secondary
analyses of survival time will be specified in an analytical plan established prior to interim analysis.
Analytical methods will also be prescribed in detail in this analytical plan. Separate data handling
criteria and a separate analytical plan will be prepared for HRQOL.
13.4. Summarizing patient registration
Patient registration data will be summarized. Discontinuations and dropouts will be summarizedbased on the handling criteria, and cumulative discontinuations and dropouts will be calculated by
the Kaplan-Meier method. To investigate balance between the treatment arms with respect todistribution of the most important background factors, background factors will be summarized withrespect to each factor. To measure the degree of balance, tests will be carried out between thetreatment arms with respect to each factor as necessary.
13.5. Summarizing and comparing treatment compliance
Treatment compliance will be summarized based on the handling criteria. Reasons for treatment
discontinuation will be summarized. The frequency and reasons for changes in treatment other than
discontinuation will be summarized.
13.6. Analysis of survival times
The cumulative survival rate will be calculated for each survival time for each treatment arm by

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the Kaplan-Meier method. Confidence intervals for the survival rate for each year from the first to
the fifth year will be calculated using Greenwood’s formula.
13.7. Supplemental analysis of survival times
Subset analyses will be performed for important prognostic factors. The R and N values using
during assignment will be included as factors, as may other factors observed to be strongly related
to survival time during a blind review. Furthermore, a Cox regression including dummy variables
and the factors above will be used to investigate the strength of the effect of prognostic factors on
survival time.
13.8. Analysis of the impact of secondary treatments on overall survival
Using an appropriate method of causal inference, there will be an exploratory investigation of
the impact of secondary treatments on overall survival after recurrence.
13.9. Analysis of adverse events
Frequencies of adverse events will be summarized for each course of each treatment arm basedon grade. Adverse events of high frequency will be investigated for their cumulative status. The
worst grade of each adverse event will be calculated for each patient, and the treatment arms
compared according to the Mantel test. Only adverse events of Grade 3 or 4 will also be
summarized.
13.10. Other analyses
HRQOL will be analyzed according to an analytical plan to be prepared separately, as statedabove. Other exploratory analyses, such as a between-study site analysis of survival times, will be
performed according to the analytical plan.
13.11. Blinded monitoring
The Steering Committee will monitor registration, treatment compliance, and survival underblinded conditions with the treatment arms masked. The Steering Committee will also investigate
the suitability of the rationale used to set the required sample size (number of events) anddetermine non-inferiority thresholds, the suitability of the interim analyses and final analysis andtiming of public release of the same, taking into consideration newly released clinical study results,
newly approved anticancer drugs/adjuvant chemotherapies deemed efficacious and the like. Whena protocol change is judged necessary, a change to the protocol will be proposed upon discussion
with the Protocol Drafting Committee and the change enacted upon deliberation and approval by
the Efficacy and Safety Evaluation Committee. The above-described examinations will not becompulsory. The blind review required to determine details of the analytical plan, such as which
variables to investigate using the Cox regression model, will be undertaken before the interim
analysis.
13.12. Interim analysis
The Efficacy and Safety Evaluation Committee will carry out an interim analysis at 1 year and 2
years after the start of registration to examine treatment compliance and occurrence of adverse
events. The Efficacy and Safety Evaluation Committee will offer advice to the Steering Committee
on discontinuation of the study and changes to the study plan if such are deemed necessary, taking

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into consideration patient registration, newly released clinical study results, newly approved
anticancer drugs/adjuvant chemotherapies deemed efficacious and the like.
The Efficacy and Safety Evaluation Committee will carry out an interim analysis of efficacy interms of overall survival upon observation of 180 events (deaths). The purpose of this interim
analysis is to avoid continued administration in a treatment arm in disadvantageous circumstances,when it does not seem possible to verify the non-inferiority of the S-1 arm against the GEM arm or
when the S-1 arm is markedly inferior to the GEM arm in terms of safety (futility). Conversely, thepurpose of this interim analysis is also to quickly release the results and see the conclusions quickly
put into clinical practice when excellent performance is observed in the S-1 arm and non-inferiority
is deemed to have already been verified (efficacy). The criterion for determining futility is a
Bayesian predictive power of 5% with respect to non-inferiority. This is equivalent to an S-1 arm to
GEM arm hazard ratio of 1.13 (log-rank test: one-sided p = 0.20). The criterion for determining
efficacy is a one-sided p-value of 0.1%. In other words, non-inferiority will be examined using
two-sided 98% confidence intervals. If non-inferiority is verified according to this criterion the S-1
arm to GEM arm hazard ratio will be 0.79 (log-rank test: one-sided p = 0.057). The Efficacy and
Safety Evaluation Committee will, based on the above-described criteria and upon considering
information such as adverse events, results of a current analysis of HRQOL, newly released clinical
trial results and newly approved anticancer drugs/adjuvant chemotherapies deemed efficacious,
offer advice to the Steering Committee to recommend either discontinuation or continuation of thestudy based on a determination of either futility or efficacy. In the event of a recommendation to
discontinue the study based on either futility or efficacy, the Efficacy and Safety Evaluation
Committee will recommend publication of the study results at the same time as the final
follow-up/final report.
Note that following Korn’s proposal26, even if the study is not discontinued at an interim
analysis, if the time interval between an interim analysis and final analysis is expected to be at least
1 year the results of the interim analysis may be publicly released once the schedule for the final
analysis and report has been stated explicitly.

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14. Ethical considerations
14.1. Patient protection
All study collaborators will conduct this study in accordance with the principles of the
Declaration of Helsinki (Japan Medical Association: http://www.med.or.jp/wma/) and according to
Ethical Guidelines for Clinical Studies (MHLW Notice No. 255:
http://www.mhlw.go.jp/topics/2003/07/tp0730-2.html).
14.2. Informed consent
14.2.1. Explanation to patients
Prior to registration, the investigator will give the patient written information that has been
approved by the IRB of the study site (the attached written information or written information
modified by the study site), and explain the below-described matters in detail and in person to thepatient.
1) An explanation of the disease name, disease staging and predicted prognosis
2) That this study is a clinical trial
The difference between the terms clinical trial and clinical practice.
3) The study design and rationale for the study (rationale with respect to significance, number ofregistered patients, necessity, objectives, etc.)
4) Details of the protocol treatment
Drug names, administration, dose, treatment cycles, duration of the entire protocoltreatment, etc.
5) Expected effects of the protocol treatment
Survival benefit, tumor regression, relief of symptoms, etc.
6) Expected adverse events, complications, sequela and how they will be handled
The severity and frequency of expected adverse events including complications, sequela
and treatment-related death, and how they will be handled when they arise.
7) Burden of costs and compensation
An explanation that costs associated with treatment will be dealt with under the healthinsurance system, and that compensation in the event of injury to health will be
proportionate with the provision of general treatment, where both costs and compensation
will be equivalent with general treatment. Also, an explanation of the burden of costs, etc.
in the case of off-label use.
8) Alternative treatment
The details, effects, toxicity, etc. of current general treatment (including palliative care) andcurrent standard treatment.
The benefits and disbenefits of choosing an alternative treatment.
9) The expected benefits and potential disbenefits to the patient of participation in the study
The benefits it is believed the patient will enjoy and the disbenefits it is believed the patient
will suffer upon participating in the study.
10) Direct access of medical history
An explanation about accepting audits such as “The direct access of medical histories by
the medical staff of other facilities with the permission of the head of the study site for the
purposes of quality control”.
11) Refusal of consent and withdrawal of consent
That the patient is free to refuse to consent to participate in the study, and that having
consented to participate in the study the patient is then free to withdraw to consent toparticipate in the study, and in either event the patient will experience no unwarranted
medical disbenefit.
12) Respect for human rights

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Maximum efforts will be taken to keep names secret and protect personal information.
13) Secondary use of data
That data may be used for a second time (meta-analysis, etc.), though in a manner that does
not connect it to any personally identifying information.
14) Inquiries
In addition to the contact details of investigators, patients will be given the contact detailsof the study site study manager and study representative (or study administrator) in
document form, and informed they are free to ask them questions about the study and thetreatment.
14.2.2. Consent
After explaining the study to the patient and confirming that the patient thoroughly understands
the content of the study, the patient will be requested to participate in the study. If the patient
herself/himself agrees to participate in the study, the investigator who explained the study and thepatient who received the explanation and consents to participate in the study will both sign and date
the attached informed consent form or an informed consent form that is in a format determined by
the study site.
Two copies of the informed consent form will be made, with one copy given to the patient
herself/himself and one copy retained by the study site coordinator. The original informed consent
form will be retained for the medical record.
14.3. Protection of privacy and patient identification
Participating study sites will not inform the data center of the name, initials, date of birth or
medical record number of registered patients.
Registered patients will be identified and cross-referenced using the registration number issued
at registration. Consequently, no information that can be used by a third party to directly identify
patients will be entered into the database of the CSPOR data center, except via the staff of the studysite or via unauthorized access of the database.
14.4. Protocol violations
Study personnel participating in this study will comply with this protocol to the extent it does notinterfere with the safety or human rights of the patient.
14.5. Approval of the study site ethical review board (institutional review board)
14.5.1. Approval at the start of study participation
This protocol and the written information for patients must be approved by the ethical review
board or IRB of each study site prior to participation in this study.
Once approved by the IRB, the principal investigator or study site coordinator of each study site
will fax the statement of IRB approval to a study administrator and the CSPOR data center. The
original copy of the statement of IRB approval will be retained by the principal investigator of thestudy site or the study site coordinator, and the faxed copies of the statement of IRB approval will
be retained by the study administrator and CSPOR data center.
Note that the written information for patients may be used after modification by the study siteand subsequent approval by the IRB of the same study site, but study sites will not be allowed tochange the content of the protocol. The same protocol will be used by all study sites. If it becomes
necessary to change the content of the protocol, the protocol used by all study sites will beamended or revised accordingly.
14.5.2. Annual renewal of IRB approval
An annual renewal of the review and approval of this protocol and the written information for

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patients by the ethical review board or IRB of each study site may or may not be performed,
according to the provisions of each participating study site. Study administrators will not request
the submission of written acknowledgment of the annual renewal of IRB approval.

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14.6. Changes to the protocol
14.6.1. Types of changes to the protocol
Before making a change (activation), an Application for Protocol Revision must be submitted toand approved by the Efficacy and Safety Evaluation Committee.
Protocol changes made after approval by the Clinical Trial Review Committee will be divided
into protocol amendments and protocol revisions. However, because this distinction will be madeby the Efficacy and Safety Evaluation Committee, all applications to the committee may be madeas an Application for Protocol Revision. Also, the addition of supplementary explanations that do
not equal a protocol change will be identified as memoranda. Definitions and handling are shown
below.
1) Amendment
A partial change to the protocol that has the potential to increase the risk to patients participatingin the study, or is related to the primary endpoint. Requires review and approval by the Efficacy
and Safety Evaluation Committee and IRB of each study site. Requires approval by a study
administrator and the head of the data center before an application for the change can be made to
the Efficacy and Safety Evaluation Committee.
The date of approval by the Efficacy and Safety Evaluation Committee will be shown on the
cover page.
2) Revision
A change to the protocol that does not have the potential to increase the risk to patients
participating in the study, and is not related to the primary endpoint. Requires review and approvalby the Efficacy and Safety Evaluation Committee. Requires approval by a study administrator andthe head of the data center before an application for the change can be made to the Efficacy and
Safety Evaluation Committee.
Review and approval by study site IRBs will be handled according to the arrangements ofindividual study sites.
The date of approval by the Efficacy and Safety Evaluation Committee will be shown on the
cover page.
3) Memorandum
A supplementary explanation of the protocol to be distributed by the study representative/study
administrators to study contributors for the purpose of reducing the variety of possible
interpretations of the protocol and in particular to call attention to certain matters; not a protocol
change. No prescribed format.
Requires approval by the study representative and head of the data center prior to distribution.
Requires a report to be made to the Efficacy and Safety Evaluation Committee either before
distribution or promptly after distribution.
Does not need to be shown on the cover page.
14.6.2. Study site IRB approval upon protocol amendment/revisionDuring the study, when the protocol or written information for patients is amended following
approval by the Efficacy and Safety Evaluation Committee, the amended protocol and written
information must be approved by the ethical review board (or IRB) at each study site.
When the change is a revision and not an amendment, the decision as to whether its review andapproval is required by study site ethical review boards (or IRBs) will be handled according toarrangements at each study site.
When an amendment has been approved by an IRB, the principal investigator or study site
coordinator of each study site will fax a copy of the IRB approval statement to a study
administrator and the CSPOR data center. The original copy of the IRB approval statement will be
retained by the principal investigator or study site coordinator, and copies retained by the study

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administrator and CSPOR data center, respectively.

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14.6.3. Correction of records forms (reproduction of section 9.1.4.)
Although the CSPOR data center and study administrators take extreme care during the
preparation of records forms, it is possible that missing or inappropriately classified required items
and the like are discovered in records forms after commencement of the study. In such cases,
records forms will be corrected upon the consent of the head of the data center and a study
administrator, provided the change does not mean the scope of the data prescribed for collection in
protocol section 8. “Items for evaluation, laboratory tests and evaluation schedule” will be
exceeded, and provided the correction is judged not to increase the clinical or financial burden on
registered patients. Corrections to records forms that do not require amendment of the protocol
itself will not be regarded as protocol amendments. Study site rules will be followed as to whether
a records form correction will be reported to the study site IRB.

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15. Monitoring and audit
15.1. Periodic monitoring
The CSPOR data center will expedite submitted data, review and make inquiries with respect tosubmitted data, correct data based on the results of such inquiries, and manage its databaseaccording to a separately established data management plan (SOPs and manual).
As a general rule, periodic monitoring will be carried out twice annually to check whether the
study is being conducted safety and according to the protocol, and whether data is being gathered
accurately.
Monitoring will take place by the central monitoring of data entered into records forms (CRFs)
collected by the CSPOR data center, and will not take place by visiting study sites to verify
submitted data against source documents.
Periodic monitoring reports prepared by the CSPOR data center will be submitted to andexamined by the study administrators, study representative and Efficacy and Safety Evaluation
Committee.
The CSPOR data center will prepare periodic monitoring reports using entered data, and prepare
analytical datasets for statistical analysis.
The objective of periodic monitoring is not to expose problems with the study and at study sites,
but to provide feedback on problems in order to improve the scientific and ethical basis of the study.
Consequently, the study administrators, study representative and Efficacy and Safety Evaluation
Committee will endeavor to resolve problems highlighted in period monitoring reports.
15.1.1. Monitored items(1) Status of accrual: Number of registered patients-cumulative/by period, all study sites/by study
site(2) Eligibility: Ineligible patients/potentially ineligible patients: study site
(3) By protocol treatment ongoing/treatment ended, reason for discontinuation/ending: study site(4) Pretreatment background factors(5) Severe adverse events: study site(6) Adverse drug reactions/adverse events(7) Protocol deviations: study site(8) Overall survival: All Registered Patients(9) Other problems relating to safety and study progress
15.1.2. Protocol deviations/violations
Protocol deviations will include treatments such as drug administration, radiation exposure andsurgical resection, laboratory tests, and toxicity/efficacy evaluations not performed according to theprovisions of the protocol.
During monitoring, as a general rule, deviations that exceed specific acceptable ranges decided
between the study administrators and study representative will be listed as “Patients with apotential deviation” in the monitoring report, and upon examination by the study administratorsand study sites attributed one of the classifications below.
1) Violation
Deviations from the provisions of the protocol will be deemed violations if they are clinicallyinappropriate, were caused by the investigator/study site, AND fall under any of the following.
(1) Impact on evaluation of a study endpoint(2) Intentional or systemic(3) The danger or deviation is of marked severity
Violations will, as a general rule, be described individually upon publication of academic
articles.

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2) Deviation
Deviations that do not fall under violations in 1), or acceptable deviations in 3).
Particular deviations will be described upon publication of academic articles if they are observedwith high frequency.
3) Acceptable range (acceptable deviation)
Deviations from protocol acceptable ranges established before or after commencement of thestudy by the study group or between the study administrators and study representative.
Deviations within prescribed acceptable ranges will not be written into monitoring reports.
15.2. Study site visit and audit
Visit and audit of study sites will be carried out as necessary.

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16. Notice
Central pathological diagnosis and checking for recurrence will not be carried out outside of thestudy sites.

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17. Study organization
Changes to this section do not require review by the Efficacy and Safety Evaluation Committee,
but do require approval by the study representative. Changes will be promptly promulgated in
document form to all participating study sites and the data center by the study administrators/study
representative.
17.1. Study representative
Katsuhiko Uesaka
Department Head, Department of Hepato-Biliary-Pancreatic Surgery, Shizuoka
Cancer Center
1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777
Tel
055-989-5222
Fax 055-989-5634
E-mail k.uesaka@scchr.jp
17.2. Study administrators
Yukiyasu Okamura
Chief Physician, Department of Hepato-Biliary-Pancreatic Surgery, Shizuoka
Cancer Center
1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777
Tel
055-989-5222
Fax 055-989-5634
E-mail yu.okamura@scchr.jp
Akira Fukutomi
Chief Physician, Department of Gastrointestinal Medicine, Shizuoka Cancer Center
1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777
Tel
055-989-5222
Fax 055-989-5634
E-mail a.fukutomi@scchr.jp
17.3. Steering Administrator
Clinical Trial Development Department, Public Interest Incorporated Foundation - Shizuoka
Industrial Foundation - Pharma Valley Center
Toshiyuki Soga (Department Director)
1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777
First floor, Research Laboratory, Shizuoka Cancer Center
Tel055-980-6322
Fax 055-980-6320
E-mail jaspac@fuji-pvc.jp
Public Interest Incorporated Foundation - Shizuoka Industrial Foundation (prior Shizuoka
Organization for Creation of Industries) is an incorporated foundation given permit to operate in
Shizuoka Prefecture according to Article 34 of the Civil Code in March of 1970 for the purpose ofmanagement innovation for SMEs, the promotion of business start ups, the strengthening ofmanagement foundations and the advancement of research and development into science andtechnology.
The Pharma Valley Center promotes world-class research and development in areas spanning

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medicine and wellness in order to improve the health of citizens of the prefecture and develop
health-related industries, and is an administrative office of the Pharma Valley Project. The
clinical trial development department works to promote the development of and promulgation ofadvanced medical care.
This study will be conducted by the Pharma Valley Center Clinical Research Development
Project, which promotes clinical research performed mainly by researchers in Shizuoka
prefecture, in order to establish evidence and promote the development of advanced medical care.
The Pharma Valley Center Clinical Research Development Project will support activities andexpenditures incurred during the conduct of the clinical study with funding obtained frominvestors sympathetic to the project.
17.4. Participating study sites
This study is a multi-center trial of postoperative adjuvant chemotherapy on a national scale.
The organization established for the purpose of this study is named the Japan Adjuvant Study
Group of Pancreatic Cancer, which plans to continue its work towards the development of
postoperative adjuvant chemotherapies in the field of hepato-biliary-pancreatic medicine
building on accumulated knowledge, experience and skills following on from the present study.

Ogaki Municipal Hospital

Department of surgery

Yuji Kaenoka

Kasugai Municipal Hospital

Department of surgery

Ryuzo
Yamaguchi

Study site
coordinator
Nobumasa
MizunoKeisuke
KitanoAtsuyuki
Maeda
ShinyaWatanabe

SoichiroMorinaga

ShinichiOhkawaYasuharu
Ikeda
Nobuyoshi
Hatanaka
Hideyuki
NogawaMasaruKonishiShojiNakamori
Hirohiko
Sakamoto

TadashiKaneshiro
Masahiro
Tanemura
Yuko
Nagashima
MasaruKonishiAtsushiMiyamoto
Hirohiko
Sakamoto

Katsuhiko
UesakaYukiyasu
OkamuraStudy site name (medical institution)
Aichi Cancer Center Hospital
Ashikawa Medical University

Kanagawa Cancer Center
Kyushu Cancer Center
Kure Medical Center
Gunma Prefectural Cancer Center
National Cancer Center Hospital East
National Hospital Organization Osaka
Minami Medical Center
Saitama Cancer Center
Shizuoka Cancer Center

Department
Department ofgastrointestinal surgery
Department ofgastrointestinal surgery

Department ofgastrointestinal surgery,
hepato-biliary-pancreatic
Department ofgastrointestinal surgery
Department of surgery
Department ofgastrointestinal surgery
Department of epigastricsurgery
Department of surgery
Department ofgastrointestinal surgery
Department of
hepato-biliary-pancreaticsurgery

Study site
study manager
Yasuhiro
Shimizu
Yohei Kitano

Shizuoka General Hospital

Department of surgery

Yusuke Kyoda

Jichi Medical University Hospital

Department ofgastrointestinal surgery

Naohiro Sata

Seirei Mikatahara General Hospital

Department of surgery

Kazunori
Ogino

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YusukeKyoda
Yasunari
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Chiba Cancer Center

Department ofgastrointestinal surgery

Hiroshi
Yamamoto

University of Tsukuba, Graduate
School of Comprehensive Human
Sciences

Department ofgastrointestinal surgery

Nobuhiro
OhkohchiTochigi Cancer Center

Department of surgery

Toyama Prefectural Central Hospital

Department of surgery

ShoichiHishinuma
Koichi
Shimizu
MasatoNaginoOsamu
Kainuma
Tatsuya Oda
Shinji
Hashimoto
MoriakiTomikawa
Koichi
Shimizu
Yukihiro
Yokoyama

Department ofgastrointestinal surgery I
Second department ofgeneral surgery(biliary-pancreatic)
Department of oncologicalsurgery
Department ofgastrointestinal andgeneral surgery
Department ofgastrointestinal surgery

Shin Ishihara

Shin
Ishihara

Satoshi Hirano

Satoshi
HiranoWataruKimuraIchiro Hirai

Hyogo Prefectural Nishinomiya
Hospital

Department of surgery

Masaki
Kashiwazaki

Kobe University Hospital

Department of
hepato-biliary-pancreaticsurgery

Yonson Ku

Kushiro City General Hospital

Department of surgery

Naoto
Hasegawa

Nagoya University Hospital
Fujita Health University
Hokkaido University Hospita;
Yamagata University
Yokohama City University

Toyohashi Municipal HospitalTokyo Women’s Medical University
Hospital
Tokyo Women’s Medical University
Medical Center East
Tokyo Womens Medical University
Yachiyo Medical Center
Shikoku Cancer Center
Hirosaki University

Department of generalsurgery
Department ofgastrointestinal surgery
Department of surgery
Department of
hepato-biliary-pancreaticsurgery
Department ofgastrointestinal surgery
Department ofgastrointestinal surgery

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Endo Itaru

Takehiko Kato
Masakazu
Yamamoto
Yoshihiko
Naritaka

Takao
Matsuyama
Masaki
Kashiwazaki
MasakoShinzeki

Takehiko
Kato
Takashi
Hatori
ShunichiShiozawa

Tatsuo Araida

TomokoMurakami

MinoruTanadaKenichiHakamada

Akinori
Asaki
Keinosuke
IshidoJASPAC 01 protocol
17.5. Steering Committee
Chairperson
MemberMemberMemberMemberKatsuhiko Uesaka

Shizuoka Cancer Center

Taira Kinoshita
Masato Nagino

National Cancer Center Hospital East
Nagoya University Hospital

Narikazu Boku
Toshiyuki Soga

St. Mariannna University
Pharma Valley Center

17.6. Efficacy and Safety Evaluation Committee
Chairperson
MemberMemberMemberNobuyuki Yamamoto
Masayuki Shinoda
Shuji Saito
Takeharu Yamanaka

Wakayama Medical University
Aichi Cancer Center Hospital

Yokohama Medical Center
National Cancer Center

17.7. Study statistician (manager of biostatistical analysis)
Yasuo Ohashi
Professor, Graduate School of Medicine and Faculty of Medicine, The Universityof Tokyo
17.8. Data center
The Public health Research Foundation (CSPOR) will be entrusted with the responsibilities ofthe data center.
Representative (head of CSPOR data center)Yasuo Ohashi
Professor, Graduate School of Medicine and Faculty of Medicine, The Universityof Tokyo/NPO Japan Clinical Research Support Unit Chief Director
1-2-13 Yushima, Bunkyo-ku, Tokyo 113-0034 (within NPO Japan ClinicalResearch Support Unit)
Tel
03-3254-8029
Fax
03-5298-8536
E-mailjaspac01@crsu.org
17.9. Protocol Drafting Committee
Chairperson
MemberMemberMemberKatsuhiko Uesaka
Narikazu Boku
Atsuyuki Maeda

Akira Fukutomi

Shizuoka Cancer Center
St. Marianna University
Ogaki Municipal Hospital
Shizuoka Cancer Center

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18. Presentation of study results
Following presentation of the results of this study to the ASCO or similar international academic
meetings, they will be submitted for publishing in an English-language journal as a research article.
The results of this study will also be presented at academic meetings within Japan as necessary.
The Steering Committee will decide who will make presentations and who will author the journal
article while taking the number of registered patients into consideration, and definitely include thethree study sites with the most registered patients in these decisions. As stated in protocol section
13.12. “Interim analysis”, the results of interim analyses may also be presented if there is expected
to be at least a 1-year interval between an interim analysis and the final analysis.

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19. References
1) Statistics and Information Department, Minister’s Secretariat, Ministry of Health, Labour andWelfare, Japan: 2005 Population Survey Report2) Sener SF, Fremgen A, Menck HR, et al. Pancreatic cancer: a report of treatment and survival
trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. J
Am Coll Surg. 1999 Jul;189(1):1-7.
3) Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic
adenocarcinoma. Am J Surg. 1993 Jan;165(1):68-72; discussion 72-3.
4) Sperti C, Pasquali C, Piccoli A, et al. Recurrence after resection for ductal adenocarcinoma of
the pancreas. World J Surg. 1997 Feb;21(2):195-200.
5) Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy
following curative resection. Arch Surg. 1985 Aug;120(8):899-903. Erratum in: Arch Surg
1986 Sep;121(9):1045.
6) Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after
curative resection of cancer of the pancreas and periampullary region: phase III trial of the
EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999 Dec;230(6):776-82;
discussion 782-4.
7) Bakkevold KE, Arnesjo B, Dahl O, et al. Adjuvant combination chemotherapy (AMF)
following radical resection of carcinoma of the pancreas and papilla of Vater--results of acontrolled, prospective, randomised multicentre study. Eur J Cancer. 1993;29A(5):698-703.
8) Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy andchemotherapy after resection of pancreatic cancer. N Engl J Med. 2004 Mar
18;350(12):1200-10. Erratum in: N Engl J Med. 2004 Aug 12;351(7):726.
9) Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for
gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial inpatients with resected pancreaticobiliary carcinoma. Cancer. 2002 Oct 15;95(8):1685-95.
10) Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit
with gemcitabine as first-line therapy for patients with advanced pancreas cancer: arandomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13.
11) W. F. Regine, K. W. Winter, R. Abrams, et al. RTOG 9704 a phase III study of adjuvant preand post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic
adenocarcinoma.J Clin Oncol (Meeting Abstracts) 2006 24: 4007.
12) Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation inpatients undergoing curative-intent resection of pancreatic cancer: a randomized controlled
trial. JAMA. 2007 Jan 17;297(3):267-77.
13) Hertel LW, Boder GB, Kroin JS, et al. Evaluation of the antitumor activity of gemcitabine(2',2'-difluoro-2'-deoxycytidine). Cancer Res. 1990 Jul 15;50(14):4417-22.
14) Masahide Fujita et al.: Antitumor activity of LY 188011 against human cancers xenografted
into nude mice (Frist report). Cancer & chemotherapy 1994;21:517-23.
15) Heinemann V, Hertel LW, Grindey GB, et al. Comparison of the cellular pharmacokinetics andtoxicity of 2',2'-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res.
1988 Jul 15;48(14):4024-31.
16) Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral
5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of
5-fluorouracil by two biochemical modulators. Anticancer Drugs. 1996 Jul;7(5):548-57.
17) Tatsumi K, Fukushima M, Shirasaka T, et al. Inhibitory effects of pyrimidine, barbituric acidand pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res.
1987 Jul;78(7):748-55.
18) Shirasaka T, Shimamoto Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicityof 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res. 1993 Sep
1;53(17):4004-9.

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19) Okada S, Ueno H, Okusaka T, et al. Phase I trial of gemcitabine in patients with advanced
pancreatic cancer. Jpn J Clin Oncol. 2001 Jan;31(1):7-12.
20) J. Furuse, T. Okusaka, A. Funakoshi, et al. A phase II study of S-1 in patients with metastatic
pancreatic cancer. ASCO Meeting Abstracts 2005 23: 4104
21) Japan Pancreas Society: Classification of Pancreatic Carcinoma. 5th Edition, Kanehara, Tokyo,
200222) Internal Union Against Cacer. UICC TNM classification of malignant tumours. Sixth edition.
Wiley-Liss, New York, 2002.
23) Brooks R. EuroQol: the current state of play. Health Policy. 1996 Jul;37(1):53-72.
24) Japanese EuroQol Development Committee. Development of the Japanese language EuroQol.
Medicine and Society. 1998;8(1):109-123.
25) Tsuchiya A, Ikeda S, Ikegami N, et al. Estimating an EQ-5D population value set: the case ofJapan. Health Econ. 2002 Jun;11(4):341-53.
26) Korn EL, Hunsberger S, Freidlin B, et al. Preliminary data release for randomized clinical
trials of noninferiority: a new proposal. J Clin Oncol. 2005 Aug 20;23(24):5831-6.

20. Appendix
・ Performance status scale (ECOG)
・ Toxicity criteria (CTCAE v3.0 Japanese translation JCOG/JSCO edition)
・ Drug package inserts
・ Written information/informed consent form
・ Complete set of records forms (CRFs)

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